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Creatine Use during Exercise in Spinal Cord Injury?



Creatine Use during Exercise in Spinal Cord Injury?

Wise Young, Ph.D, M.D.

W. M. Keck Center for Collaborative Neuroscience

Rutgers University, Piscataway, NJ 08542

http://sciwire.com, wisey@pipeline.com


Creatine is a metabolite that is normally present in high concentrations in muscle and brain (Puri, et al. 1998).  Discovered in 1835, when a French scientist discovered this constituent of muscle (Demant & Rhodes, 1999), creatine is the substrate for creatine phosphate, a major source of energy for cells.  Oral creatine supplementation increases creatine levels in normal human muscles (Perskey & Brazeau, 2001), as well atrophied muscles after spinal cord injury in rats (Dupont-Versteedgen, et al. 1998).  Athletes often take creatine monohydrate orally to improve muscle power and reduce muscle fatigue during training (Smith & Wilder, 1999; Maughan, 2002), as well as improve oxygen uptake (Jones, et al., 2002).


Creatine therefore may be useful for preventing atrophy or restoring atrophic muscles in spinal cord injury, multiple sclerosis, and other disorders that cause.    Although several studies suggest that creatine increases muscle power and bulk, as well as reduces fatigue in athletes, the use of creatine is controversial.  Many recent studies, however, have provided strong laboratory and clinical evidence of the beneficial effects of creatine for rehabilitation and athletic performance.

Effects of Creatine on Athletic Performance


Oral creatine supplementation significantly enhanced high intensity, intermittent exercise performance in competitive squash players (Romer, et al. 2001) and elite female soccer players (Cox, et al., 2002).  Tarnovsky, et al. (2000) compared the effects of creatine supplementation on men and women and found no gender effects.  However, creatine may not be as effective in aged individuals (Tarnopolsky, 2000).  Interestingly, creatine supplementation (25 g/day) did not seem to have much effect on plasma creatine levels or muscle metabolic response (Schuback, et al. 2000).  Nelson, et al. (2000) showed that creatine supplements increase performance on graded exercise on a cycle ergometer test.  Burke, et al. (2001) showed that men taking whey protein (1.2 g/kg/day) and creatine monohydrate (0.1 g/kg/day) showed a greater increase in lean body mass, greater bench press strength, and greater knee extension torque than men receiving whey protein alone, and those receiving whey protein alone showed significantly greater improvement on these measures than men that received only a placebo.  These beneficial effects of creatine were maintained for up to 6 weeks after the whey and creatine were stopped. 


Creatine supplementation appears to be as good or better than dextrose-protein supplementation for improving muscle performance in able-bodied athletes.  For example, Tarnopolsky, et al. (2001) compared the effects of creatine-carbohydrate supplementation with a protein-carbohydrate supplement in 19 young healthy male subjects.  The  subjects all performed 8 weeks of weight training (1 hour/day and 6 days/week).  All the subjects showed significant increase in muscle mass but those receiving creatine monohydrate (10g) and dextrose (75 g) gained 4.3 kg (5.4%) compared to 1.9 kg (2.4%) in those that received the protein-carbohydrate supplement but both showed similar increase in fat-free mass, maximum strength on 16 weight training exercises, and isokinetic knee extension torque.  


Many other studies have reported that creatine supplementation enhances intermittent work performance (Hamilton, et al., 2000; Stout, et al., 2000; Stone, et al., 1999; Bosco, et al. 1997; Grindstaff, et al., 1997; Prevost, et al., 1997; Volek, et al., 1997; Casey, et al. 1996; Rossiter, et al. 1996; Febbraio, et al. 1995).   Creatine supplementation should enhance high-intensity, short-term, muscle activity that depends primarily on phosphocreatine levels.  For this reason, creatine should show beneficial effects on exercise bouts with limited recovery periods between repetitions.  Miura, et al. (1999) showed that creatine (20 g/day) indeed increased the power-duration curve of subjects undergoing high-intensity short-duration cycle ergometer exercise. 


Creatine should not enhance performance in tasks dependent on aerobic glycolysis or overall endurance (Williams & Branch, 1998).   Vandeburie, et al. (1998) studied the effects of creatine on endurance capacity and sprint power in 12 cyclists who were tested for endurance during 2.5 hours cycle to exhaustion at a predetermined 4 mM lactate threshold, followed by five maximal 10-second sprints separated only by 2 minute recovery intervals.  Creatine loading had no effect on endurance time but improved intermittent sprint capacity at the end of endurance exercise to fatigue.  Similar results have been reported by other investigators (Smith, et al. 1998; McNaughton, et al. 1998).  Syrotuik, et al. (2001) assessed the effects of 0.3 g/kg loading dose followed by 5 weeks maintenance (0.03 g/kg/day) of creatine monohydrate.  In 22 rowers who trained with continuous and interval rowing and resistance training, creatine supplementation did not change body composition, rowing performance and times, or strength.  However, after five week of training, all the subjects showed significant improvements in almost all measured performance parameters but there was no difference between the creatine-treated and placebo groups.  


In summary, although much data supports a performance enhancement effect of creatine supplementation, the effects on performance appear to be most prominent under certain exercise conditions (Terjung, et al., 2000) and creatine supplements appear to be most helpful for performance of short and repeated bouts of strength activities.  Creatine supplements do not seem to increase maximal isometric strength, rate of maximal force production, or aerobic exercise performance. 

Creatine Effects on Muscle Rehabilitation


Creatine monohydrate improves exercise capacity of people with spinal cord injury.  At the Miami Project, Jacobs, et al. (2002) randomized 16 men with cervical spinal cord injury to creatine monohydrate (20g/day) or placebo for 7 days, followed by 21 days of no treatment, and then switched the treatments groups for 7 days.  They measured peak arm power output, fatigue time, heart rate, respiratory rate, tidal volume, and other metabolic parameters during the exercise.  They found that those subjects taking creatine had greater oxygen consumption, higher carbon dioxide output, and tidal volumes than those subjects on placebo.  Note that the subjects received creatine for only 7 days and improved arm power and fatigue may not show with such a short period of treatment.  However, the treatment does seem to improve the capability of the subjects to exercise intensively and reach higher peak levels of oxygen utilization, carbon dioxide production, and respiratory parameters.


Creatine supplementation also significantly facilitates rehabilitation of disuse atrophy, or muscle atrophy associated with non-use.  Hespel, et al. (2001) studied the effects of creatine supplements on young adults (n=22) subjected to leg immobilization for 2 weeks with a cast and then rehabilitated with exercise over a 3-10 week period.  They found that immobilization reduced the quadriceps size by 10% and strength by 25%.  The creatine-treated subjects regained muscle size and strength significantly faster than untreated subjects.


Creatine apparently has beneficial effects in diseases that cause muscle atrophy.  Patients with McArdle disease (myophosphorylase deficiency) reported that creatine supplement (five days of high dose 150 mg/kg/day and 5 weeks of low dose (60 mg/kg/day) improved both muscle power and phosphocreatine depletion in muscle (Vorgerd, et al. 2000).    Ikeda, et al. (2002) recently showed that creatine monohydrate increased grip strength, reduced forelimb contractures, and increased bicep muscle weights in Wobbler mice, a strain of mouse that is a model of muscular dystrophy. 


Creatine is beneficial in disorders of creatine synthesis and degenerative diseases of muscles and other tissues.  Abnormalities of creatine kinase play a major role in a variety of diseases, including muscle, brain, cardiac, and renal diseases, as well as cancer (Wyss, et al., 2000).  Creatine supplementation may reduce fatigue and improve strength in mitochondrial diseases (Tarnopolsky, et al. 1997) and myophosphorylase deficiency or McArdle’s disease (Vorgerd, et al. 2000).  Walter, et al. (2000) randomized36 patients with various types of muscular dystrophies to creatine or placebo for 8 weeks and found mild but significant improvement in muscle strength and activities of daily living.  Tarnopolsky & Parise (1999) found that patients with neuromuscular disease have lowered levels of phosphocreatine and ATP levels.  Tarnopolsky & Martin (1999) reported that creatine monohydrate increases strength in patients with neuromuscular disease.


The effects of creatine monohydrate supplements on older people are unclear.  Although creatine monohydrate supplements increase muscle mass, fat-free mass, and enhance high-intensity exercise performance in young healthy men and women, a few studies of creatine monohydrate in aged individuals have not shown convincing evidence of its beneficial effects  on muscle mass or function Tarnopolsky (2000).   Berman, et al. (1998) assessed the effect of 20g daily oral creatine monohydrate with and without weight training.  While training itself improved performance, creatine supplementation did not.   This reduced effect of creatine monohydrate supplement in aged people may account for why creatine supplementation did not work for all people with rheumatoid arthritis (Willer, et al., 2000).

Optimal Dose and Duration of Creatine Supplementation


The effects of creatine supplementation depend on the individual.  Normally, the body synthesizes creatine from the amino acids glycine, arginine, and methionine in the kidneys, liver, and pancreas (Demant & Rhodes, 1999).  In muscle, about 40% of creatine is free while 60% is phosphorylated.  The average individual turns over approximately 2-4 grams of creatine.  Thus, 5-6 grams of creatine should be more than enough to supply and replace creatine in the muscles. 


Some evidence (Silber, 1999) indicates that the body contains homeostatic mechanisms that inhibit the uptake and use of creatine when certain levels have been achieved.  There is no evidence that creatine intake greater than 20-30 g/day has any additional benefits on creatine uptake or performance (Casey & Greenhaff, 2000).   Individuals who have total creatine levels of 150 mmoles/kg dry mass usually do not take up additional creatine uptake and show no performance increment.   This limits the potentially deleterious side effects of creatine overdose.  The beneficial effects of creatine clearly depend on the existing levels of creatine from both exogenous and endogenous sources.


 The optimal duration of creatine supplementation is not known.  Short-term (4-7 days) creatine supplementation may not enhance performance of certain exercises (Odland, et al. 1997; Javierre, et al. 1997).   Green, et al. (2001) found that creatine supplementation for 6 days did not change mean muscle power or peak power in physically active men working on weight-lifting devices.  Mujika, et al. (1996) reported that 5-day administration of creatine monohydrate to 20 highly trained swimmers did not show any significant differences in performance times or lactate accumulation although the treated group had lower post-exercise blood ammonia levels.  Barnett, et al. (1996) showed that a four-day period of creatine supplement did not raise resting muscle creatine levels or enhance multiple sprint performance.  Redondo, et al. (1996) and Terrillion et al. (1997) found that oral creatine supplements for 7 days did not enhance sprinting or 700-m maximal running performance.


Although most research on creatine supplementation has focused on muscles, many other tissues have high levels of creatine or take up ingested creatine.  Ipsiroglu, et al., (2001) examined tissue creatine concentrations in a range of tissues of various animal species after oral creatine supplementation.  Presupplementation total creatine levels were highest in brain, skeletal, and heart muscle (10-22 µmol/g wet weight) and lowest in liver, kidney, and lung (5-8 µmol/g).  Supplementation increased total creatine by only 15-55% in organs with high levels before supplementation but dramatically increase creatine levels by 250-500% in organs with low presupplementation levels.  Dechent, et al. (1999) reported that creatine supplementation for four weeks (20 grams/day) significantly increased brain creatine levels by 8.7% but with considerable variability (3.5-13.3%) in healthy human subjects.


The body turnover rate of creatine is typically 2.5-3.0 grams per day and perhaps as high as 5-6 grams per day for athletes undergoing high-intensity training.  One possible approach to creatine supplementation is to take a loading dose of 20 grams per day in 4 divided doses for a week and then maintain that level with 6 grams per day for the duration of the exercise period.  Creatine is plentiful in meat (Jacobs, 1999).  A kilogram of steak may contain several grams of creatine.  While peak plasma creatine levels were lower after meat ingestion than creatine monohydrate ingestion, plasma creatine levels were maintained for longer (Harris, et al. 2002).    

Mechanisms of Creatine-induced Muscle Enhancement


The mechanism by which oral creatine supplementation increases muscle strength is not clear.  The mechanism apparently does not involve increased synthesis of muscle protein.  Parise, et al. (2001) examined the effects of creatine monohydrate (20 g/day for 5 days followed by 5 g/day for 3-4 days) on protein metabolism, compared against placebo (glucose), in young healthy men and women.  The oral creatine supplement significantly increased total muscle creatine levels by 13.1% and reduced leucine oxidation but did not increase the rate of muscle incorporation of radioactive leucine.  Thus, oral creatine may reduce the breakdown of muscle but does not increase the amount of protein synthesis in muscles.  Likewise, short-term creatine supplementation does not alter the hormonal response to resistance training, suggesting that it is not working by changing hormonal levels (Op ‘t Eijnde & Hespel, 2001).  Creatine supplementation (25 g/day) also does not alter blood lipids levels even though it significantly increased body mass and fat-free mass (Volek, et al., 2000).


Orally ingested creatine accumulates in muscle where it is phosphorylated by creatine kinase to become a source of energy. Harris, et al. (1992) showed that orally administered creatine uptake into muscles was greatest during the first 2 days of supplementation.   Wiedermann, et al. (2001) studied the influx of orally ingested creatine in normal volunteers, using 31P saturation-transfer nuclear magnetic resonance spectroscopy to measure muscle phosphocreatine (PCr).  The volunteers received 20 g/day of creatine monohydrate daily for 6 days.  Parallel to improved muscle performance during maximal intermittent exercise, they found a 23% increase in PCr in muscles from 28.5±2.7 to 34.9±2.8 mM.  Other metabolites (including inorganic phosphates, free intracellular Mg, and cytosolic pH) did not change.  Activity of creatine kinase, the enzyme that adds phosphorus to creatine to form PCr, did not change.  This suggests that the ingested creatine is taken into muscle and phosphorylated to provide additional energy source to muscles, accounting for the improved muscle performance (Kreider, et al., 1998).


Dangott, et al. (2000) reported that creatine monohydrate supplementation of rats significantly increased the number of new nuclei in the muscles of rats treated with creatine monohydrate, compared to rats that did not.  They concluded that the supplement increased muscle satellite cell activity and increased muscle bulk.  This study, however, has not been replicated by any other laboratory and must be considered preliminary. 


Creatine may alter general metabolism of the body.  For example, Rico-Sanz & Mendez Marco (2000) showed that creatine supplementation (20 g/day) markedly increases oxygen consumed in young men, reduces blood ammonia accumulation, and increased the time required to reach exhaustion during exercise.   Jacobs, et al. (1997) found that creatine increases anaerobic capacity and maximum accumulated oxygen deficits.  Jones, et al. (2002) showed that creatine supplementation significantly increased oxygen uptake during submaximal cycle exercise.  Arciero, et al. (2001) randomized 30 healthy male volunteers to 3 treatments:  creatine, creatine+training, placebo+training.  They found significant increases in total and fat-free body mass, muscular strength, peripheral blood flow, and resting energy expenditure, as well as reduced blood cholesterol. 


Earnest, et al. (1996) reported that purified creatine monohydrate reduces blood lipids in men and women.  They gave 34 subjects either 5 grams of creatine plus one gram of glucose or a gram of glucose alone four times a day for 5 days and then twice a day for 51 days.  All the subjects had total blood cholesterol concentrations exceeding 200 mg/dl.  Cholesterol did not change while triacylglycerol and very low-density lipoprotein C levels fell by 23 and 22% by weeks 4 and 8 and remained attentuated by 26% at week 12.  In women, blood urea nitrogen increased slightly from 11.8±0.7 to 13.8±0.7 mg/dl.  Otherwise, there was no change in other lipoprotein-C, total cholesterol to high-density lipoprotein ratios, glucose, creatinine, body mass, or body mass index between the treatment groups.


Creatine has several other effects on muscles that are not well understood.  For example, it facilitates muscle relaxation and strength of knee extension but not the arms.  For example, Van Leemputte, et al. (1999) studied the maximum torque, contraction, and relaxation time of 3-second elbow flexion interpersed with 10-second rest periods.  They found that creatine loading (4-5 g/day) did not affect maximum torque or contraction but reduced relaxation time consistently by about 20%.  Likewise, Urbanski, et al. (1999) assessed the effects of creatine loading (5 g of creatine monohydrate + 3 g of dextrose) performance of ten college-age males in a number of strength exercises.  They found that creatine increased the maximal isometric strength and time to fatigue for knee extension but not handgrip, concluding that creatine increases strength only of large muscle masses. 

Creatine Effects on Non-Muscle Tissues


The brain contains very high concentrations of creatine.  Defects of creatine synthesis (van der Knaap, et al. 2000) present with developmental regression, extrapyramidal symptoms, and intractable epilepsy.  Stockler, et al. (1996) treated an infant with guanidinoacetate methyltransferase deficiency, an enzyme that is essential for storage and transmission of phosphate bound energy in muscle and brain, showing that long-term oral administration of creatine monohydrate (4-8 grams per day) substantially improved clinical neurological symptoms and eliminated magnetic resonance abnormalities in the globus pallidus and electroencephalographic abnormalities.  Similarly, creatine supplement may have stabilized the progression of a 19-year old patient with early onset Leigh disease manifesting as severe extrapyramidal disorders with generalized dystonia and choreoathetosis associated with cytochrome oxidase deficiency (Cacic, et al., 2001).  Likewise, creatine supplementation was effective in two cases of brain creatine deficiency (Bianchi, et al. 2000) but was ineffective in a case of possible creatine transporter deficiency (Cecil, et al., 2001). 


Creatine may be beneficial for other brain and spinal cord disorders, including Huntington’s and Parkinson’s disease (Persky & Brazeau, 2001; Tarnopolsky, 2000).  Ikeda, et al. (2000) reported that oral ingestion of creatine monohydrate protects mice with mutant superoxide dismutase against motoneuron degeneration, a model of amyotrophic lateral sclerosis.  Wilken, et al. (2000) reported that creatine supplementation prevents ATP depletion in anoxic neonatal mice brainstems.  Creatine also reduces changes in brain water diffusion changes (Wick, et al., 1999) and cerebral metabolite concentrations (Michaelis, et al., 1999) in rat brains after transient global ischemia. 


The heart also contains high levels of creatine.  Vona-Davis, et al. (2002) examined the effects of creatinine on cardiac function in rats that had acute endotoxemia induced by bacterial endotoxin.  Creatine applied to isolated hearts of saline-treated rats produced a significant negative inotropic effect, reducing left ventricular developed pressure by 30% at the lowest concentration (1 mM) and by 50% in the highest concentration (10 mM) creatine tested.  Endotoxin treatment significantly reduced phosphocreatine/ATP and phosphocreatine/Pi ratios in hearts by 4 hours after endotoxin administration.  These data suggest that creatine not only does not contribute to myocardial preservation in endotoxemia but also may have deleterious effects of cardiac function of normal rats. 


Finally, creatine and creatine analogs such as cyclocreatine have anti-tumor (Jeong, et al. 2000), anti-viral, and anti-diabetic effects, and protects tissues against hypoxic, ischemic, neurodegenerative, or muscle damage.  The mechanism of these effects are not well understood.  Maril, et al. (1999) studied the effects of cyclocreatine and Na co-transport in human breast cancer cells, finding that the cyclocreatine has approximately 10-fold greater affinity to the creatine transporter cancer cells that are resistant to adriamycin than those that are not.  Passive diffusion of cyclocreatine was also higher by 3-4 fold in the resistant cells.  The transport of cyclocreatine was accompanied by a rapid increase in intracellular Na and may explain the ability of cyclocreatine to cause selective cell swelling and death of these cells.


Potential Side Effects of Creatine Supplementation


Few formal toxicity studies have been carried out to evaluate potential side-effects of creatine supplementation (Benzi & Ceci, 2001).  Creatine supplements are not well-controlled with respect to contaminants.  For example, commercial creatine monohydrate may contain variable amounts of dicyandiamide, dihydrotrizines, creatinine, and ions.  Creatine also is mostly commonly isolated from bovine tissues; due to fears of bovine spongiform encephalopathy, French authorities forbade the sale of products containing creatine.   


Athletes often consume 20 grams of creatine monohydrate per day for several weeks before and during intensive training and some have taken 10 grams per day of creatine for many months or even years.  Poortmans & Francaux (2000) points out that despite multiple media reports of adverse effects of creatine supplement, there is no well-documented report of adverse effects of creatine supplements.  The only change that has been more or less consistently found by many groups is an increase in fat-free body mass (Mihic, et al. 2000).  Gastrointestinal disturbances and muscle cramps have been reported occasionally in healthy individuals and several wrestlers who have died or have complications from dehydration have taken creatine although the connection to creatine is not clear.  Although anecdotal reports of liver or kidney dysfunction have been suggested, no study has shown such effects in small cohorts of athletes that have taken a month or more of creatine supplements (Poortmans, et al. 1997). 


The cause of the increase in body mass associated with creatine supplementation is not well-understood.   Saab, et al. (2002) recently used magnetic resonance spectroscopy to assess muscles in subjects that took 20 grams per day of creatine for five days, compared against placebo controls.  They found changes consistent with increases in intracellular water.    Parise, et al., (2001) showed that creatine supplementation increased total and phosphocreatine in muscles but did not increase protein synthetic rate measured from leucine uptake but reduced leucine oxidation (-20%) and plasma leucine appearance in men but not in women, suggesting that creatine may have anticatabolic actions on some proteins in men.  Because several studies have shown increased side-products of muscle metabolism and greater intracellular water content of muscles, and there have been some dehydration deaths in wrestlers taking creatine, it is a good idea to drink plenty of water with the creatine. 


Schilling, et al. (2001) assessed the long-term safety effects of supplementing athletes with about 10 grams per day for 0.8-1.0 years and >1.0 years, compared against placebo.  Blood chemistry, clinical examinations, and hormonal levels were measured, as well as body mass, body composition, and resting heart rate and blood pressure.  Long-term creatine supplementation did not change any of the measured parameters beyond normal limits although it did increase blood creatinine and total protein levels.  Kreider, et al. (1998) assessed the effects of a mixture of 15.75 grams per day of creatine phosphate on 25 NCAA division IA football players, matched against similar players that received a placebo without creatine.  They found significant increases in body mass, fat/bone-free body mass, gains in bench press lifting and other weight-lifting performance, and sprint performance but no change in hematological parameters nor subjective side-effects.   Volek, et al. (2001) tested the effects of creatine supplement on men undergoing repeated sprint cycle performance in heat and found no evidence of adverse symptoms including muscle cramps.  Likewise, Volek, et al. (2000) found no effect of heavy resistance training and creatine supplementation on blood lipids.


In doses of 20 g/day, creatine supplementation appears to be well tolerated by people with a variety of disorders over periods of several weeks.  For example, creatine monohydrate had no significant deleterious effects on exercise performance, eye movements, or activities of daily living in people with mitochondrial disease (Klopstock, et al. 2000).  Acute creatine loading increases fat-free mass but apparently does not affect blood pressure, plasma creatine levels, or creatine kinase activity in men and women (Mihic, et al., 2000).   It does not affect growth hormone levels (Op’t ijnd & Hespel, 2002) or blood lipids (Volek, et al. 2000).



Creatine is an important energy substrates for the muscle and brain.  Many randomized studies have provided suggestive data that creatine enhances athletic performance.  Short periods of creatine supplementation does not seem to increase endurance or aerobic performance.  However, much evidence indicate that creatine supplementation improves performance of repeated bouts of short and intense strength exercises. 


Creatine supplementation may facilitate rehabilitation of neurological conditions and muscular atrophy.  One study indicated that creatine monohydrate for a week increased oxygen consumption, produced greater carbon dioxide output, and improved respiratory tidal volumes in people with spinal cord injury.  Another suggested that creatine supplements retards or reverses rebuilding of atrophied muscles associated with leg casting.  Creatine also has significant beneficial effects in patients who have creatine deficiency.


The optimal dose and duration of creatine supplementation depends on the individual.   The body synthesizes creatine and meat contains relatively high concentrations of creatine.  The daily body turnover of creatine is 2-4 grams.  There is no evidence that creatine intake greater than 20-30 g/day has any additional beneficial effects of creatine uptake by muscle or performance.  A 5-7 days period of high-dose (20 gram/day) creatine followed by a maintainance dose of 5 grams  of creatine per day during the exercise period is reasonable. 


Orally ingested creatine is taken up by muscle.  The creatine does not appear to stimulate protein synthesis although one study suggested that the creatine may stimulate muscle satellite cells to produce more cells.  The creatine is phosphorylated in the muscle.   Creatine is also taken up by other tissues where it may exert a number of other effects, including improvement of oxygen consumption and reduction of blood lipids.


Creatine has major effects on the brain and the heart.  In patients who might be short of creatine or have a disease that reduces creatine levels, creatine supplement may have dramatic effects.  Creatine and creatine analogs also have been reported to have anti-tumor effects.  In particular, an analog of real-time called cyclocreatine appears to increase Na and death of tumor cells.


Despite its important role in energy metabolism in many tissues, creatine supplementation has had remarkably consistent safety record.  Athletes often consume 20 grams of creatine monohydrate per day for weeks, months, and even years without any well-substantiated report of adverse side-effects.  Although anecdotal reports of muscle cramps and hormonal effects abound, controlled clinical studies have not reported such effects.


Thus, creatine appears to be a relatively safe dietary supplement that may facilitate rehabilitation of atrophied muscles and enhance exercise therapies.  Side effects are minimal perhaps because the creatine-loaded tissues do not take up additional creatine.  Creatine does not affect growth hormone or other hormones and there is no convincing data that it causes kidney or liver damage.



References Cited


  Arciero PJ, Hannibal NS, 3rd, Nindl BC, Gentile CL, Hamed J and Vukovich MD (2001). Comparison of creatine ingestion and resistance training on energy expenditure and limb blood flow. Metabolism. 50 (12): 1429-34. Summary: This study determined the effects of 28 days of oral creatine ingestion (days 1 to 5 = 20g/d; [5 g 4 times daily]: days 6 to 28 = 10 g/d; [5 g twice daily]) alone and with resistance training (5 hours/week) on resting metabolic rate (RMR), body composition, muscular strength (1RM), and limb blood flow (LBF). Using a double-blind, placebo-controlled design, 30 healthy male volunteers (21 +/- 3 years; 18 to 30 years) were randomly assigned to 1 of 3 groups; pure creatine monohydrate alone (Cr; n = 10), creatine plus resistance training (Cr-RT; n = 10), or placebo plus resistance training (P-RT; n = 10). Body composition (DEXA, Lunar DPX-IQ), body mass, bench, and leg press 1RM (isotonic), RMR (indirect calorimetry; ventilated hood), and forearm and calf LBF (venous occlusive plethysmography) were obtained on all 30 subjects on 3 occasions beginning at approximately 6:00 AM following an overnight fast and 24 hours removed from the last training session; baseline (day 0), and 7 days and 29 days following the interventions. No differences existed among groups at baseline for any of the variables measured. Following the 28-day interventions, body mass (Cr, 73.9 +/- 11.5 v 75.6 +/- 12.5 kg; Cr-RT, 78.8 +/- 6.7 v 80.8 +/- 6.8 kg; P <.01) and total body water (Cr, 40.4 +/- 6.8 v 42.6 +/- 7.2 L, 5.5%; Cr-RT, 40.6 +/- 2.4 v 42.3 +/- 2.2 L, 4.3%; P <.01) increased significantly in Cr and Cr-RT, but remained unchanged in P-RT, whereas, fat-free mass (FFM) increased significantly in Cr-RT (63 +/- 2.8 v 64.7 +/- 3.6 kg; P <.01) and showed a tendency to increase in Cr (58.1 +/- 8.1 v 59 +/- 8.8 kg; P =.07). Following the 28-day period, all groups significantly increased (P <.01) bench (Cr, 77.3 +/- 4 v 83.2 +/- 3.6 kg; Cr-RT, 76.8 +/- 4.5 v 90.5 +/- 4.5 kg; P-RT, 76.0 +/- 3.4 v 85.5 +/- 3.2 kg), and leg press (Cr, 205.5 +/- 14.5 v 238.6 +/- 13.2 kg; Cr-RT, 167.7 +/- 13.2 v 238.6 +/- 17.3 kg; P-RT, 200.5 +/- 9.5 v 255 +/- 13.2 kg) 1RM muscular strength. However, Cr-RT improved significantly more (P <.05) on the leg press 1RM than Cr and P-RT and the bench press 1RM than Cr (P <.01). Calf (30%) and forearm (38%) LBF increased significantly (P <.05) in the Cr-RT, but remained unchanged in the Cr and P-RT groups following the supplementation period. RMR expressed on an absolute basis was increased in the Cr (1,860.1 +/- 164.9 v 1,907 +/- 173.4 kcal/d, 2.5%; P <.05) and Cr-RT (1,971.4 +/- 171.8 v 2,085.7 +/- 183.6 kcal/d, 5%; P <.05), but remained unchanged from baseline in P-RT. Total cholesterol decreased significantly in Cr-RT (-9.9%; 172 +/- 27 v 155 +/- 26 mg/dL; P <.01) compared with Cr (174 +/- 46 v 178 +/- 43 mg/dL) and P-RT (162 +/- 32 v 161 +/- 36 mg/dL) following the 28-day intervention. These findings suggest that the addition of creatine supplementation to resistance training significantly increases total and fat-free body mass, muscular strength, peripheral blood flow, and resting energy expenditure and improves blood cholesterol. Exercise Science Department, Skidmore College, Saratoga Springs, NY, USA.

  Barnett C, Hinds M and Jenkins DG (1996). Effects of oral creatine supplementation on multiple sprint cycle performance. Aust J Sci Med Sport. 28 (1): 35-9. Summary: This study examined the influence of oral creatine monohydrate supplementation on repeated 10 s cycle ergometer sprint performance. Seventeen recreationally active males (mean +/- SD age, body mass, height, and peak oxygen uptake = 20.5 +/- 1.2 yr, 72.1 +/- 10.3 kg, 176.8 +/- 6.6 cm and 3.87 +/- 0.91 l.min-1, respectively) participated in the 16 day experiment. All subjects initially completed a VO2peak test and were then administered glucose (4 x 10 g per day) in a single blind fashion for four days, after which they completed the first series of multiple sprints (7 x 10 s). Following the sprints, subjects were matched on sprint performance and divided into two groups (n = 8, placebo (Pl); and n = 9, creatine (Cr)). For the following four days, diets were supplemented with either Cr (4 x 70 mg.kg-1 body mass per day mixed with 5 g glucose) or glucose (4 x 10 g per day); supplementation during this phase was double-blind. Subjects then repeated the multiple sprint and VO2peak tests. Measures of peak power output (PPO), mean power output (MPO), end-power output (EPO), and percent power decline were recorded during the sprints. Each 10 s sprint was separated by 30 s of passive recovery except for sprints five and six which were separated by five minutes. Venous blood was sampled at rest, immediately after sprint five, before sprint six, and following sprint seven for the analysis of plasma lactate and blood pH. Expired air was sampled for five minutes following sprint seven for the calculation of post-exercise VO2. Analysis of variance revealed that four days of Cr supplementation did not influence multiple sprint performance, plasma lactate, blood pH and excess post-sprint oxygen consumption. Furthermore, VO2peak was unchanged following Cr supplementation. The data suggest that either the four day period of Cr supplementation failed to significantly raise resting muscle [Cr], or that multiple sprint performance was not enhanced by increases in resting muscle [Cr]. Department of Human Movement Studies, University of Queensland.

  Becque MD, Lochmann JD and Melrose DR (2000). Effects of oral creatine supplementation on muscular strength and body composition. Med Sci Sports Exerc. 32 (3): 654-8. Summary: PURPOSE: The purpose of this investigation was to examine the effects of 6 wk of oral creatine supplementation during a periodized program of arm flexor strength training on arm flexor IRM, upper arm muscle area, and body composition. METHODS: Twenty-three male volunteers with at least 1 yr of weight training experience were assigned in a double blind fashion to two groups (Cr, N = 10; Placebo, N = 13) with no significant mean pretest one repetition maximum (IRM) differences in arm flexor strength. Cr ingested 5 g of creatine monohydrate in a flavored, sucrose drink four times per day for 5 d. After 5 d, supplementation was reduced to 2 g x d(-1). Placebo ingested a flavored, sucrose drink. Both drinks were 500 mL and made with 32 g of sucrose. IRM strength of the arm flexors, body composition, and anthropometric upper arm muscle area (UAMA) were measured before and after a 6-wk resistance training program. Subjects trained twice per week with training loads that began at 6RM and progressed to 2RM. RESULTS: IRM for Cr increased (P < 0.01) from (mean +/- SD) 42.8 +/- 17.7 kg to 54.7 +/- 14.1 kg, while IRM for Placebo increased (P < 0.01) from 42.5 +/- 15.9 kg to 49.3 +/- 15.7 kg. At post-test IRM was significantly (P < 0.01) greater for Cr than for Placebo. Body mass for Cr increased (P < 0.01) from 86.7 +/- 14.7 kg to 88.7 +/- 13.8 kg. Fat-free mass for Cr increased (P < 0.01) from 71.2 +/- 10.0 kg to 72.8 +/- 10.1 kg. No changes in body mass or fat-free mass were found for Placebo. There were no changes in fat mass and percent body fat for either group. UAMA increased (P < 0.01) 7.9 cm2 for Cr and did not change for Placebo. CONCLUSION: Creatine supplementation during arm flexor strength training lead to greater increases in arm flexor muscular strength, upper arm muscle area, and fat-free mass than strength training alone. Southern Illinois University at Carbondale, Department of Physical Education, 62901-4310, USA. mdbecque@siu.edu.

  Benzi G and Ceci A (2001). Creatine as nutritional supplementation and medicinal product. J Sports Med Phys Fitness. 41 (1): 1-10. Summary: Because of assumed ergogenic effects, the creatine administration has become popular practice among subjects participating in different sports. Appropriate creatine monohydrate dosage may be considered a medicinal product since, in accordance with the Council Directive 65/65/EEC, any substance which may be administered with a view to restoring, correcting or modifying physiological functions in humans beings is considered a medicinal product. Thus, quality, efficacy and safety must characterise the substance. In addition, the European Court of Justice has held that a product which is recommended or described as having preventive or curative properties is a medicinal product even if it is generally considered as a foodstuff and even if it has no known therapeutic effect in the present state of scientific knowledge. In biochemical terms, creatine administration increases creatine and phosphocreatine muscle concentration, allowing for an accelerated rate of ATP synthesis. In thermodynamics terms, creatine stimulates the creatine-creatine kinase-phosphocreatine circuit, which is related to the mitochondrial function as a highly organised system for the control of the subcellular adenylate pool. In pharmacokinetics terms, creatine entry into skeletal muscle is initially dependent on the extracellular concentration, but the creatine transport is subsequently downregulated. In pharmacodynamics terms, the creatine enhances the possibility to maintain power output during brief periods of high-intensity exercises. In spite of uncontrolled daily dosage and long-term administration, no researches on creatine monohydrate safety in humans were set up by standardised protocols of clinical pharmacology and toxicology, as currently occurs in phases I and II for products for human use. More or less documented side effects induced by creatine monohydrate are weight gain; influence on insulin production; feedback inhibition of endogenous creatine synthesis; long-term damages on renal function. A major point that related to the quality of creatine monohydrate products is the amount of creatine ingested in relation to the amount of contaminants present. During the industrial production of creatine monohydrate from sarcosine and cyanamide, variable amounts of contaminants (dicyandiamide, dihydrotriazines, creatinine, ions) are generated and, thus, their tolerable concentrations (ppm) must be defined and made consumers known. Furthermore, because sarcosine could originate from bovine tissues, the risk of contamination with prion of bovine spongiform encephalopathy (BSE or mad-cow disease) can t be excluded. Thus, French authorities forbade the sale of products containing creatine. Creatine, as other nutritional factors, can be used either at supplementary or therapeutic levels as a function of the dose. Supplementary doses of nutritional factors usually are of the order of the daily turnover, while therapeutic ones are three or more times higher. In a subject of 70 kg with a total creatine pool of 120 g, the daily turnover is approximately of 2 g. Thus, in healthy subjects nourished with fat-rich, carbohydrate, protein-poor diet and participating in a daily recreational sport, the oral creatine monohydrate supplementation should be of the order of the daily turnover, i.e., less than 2.5-3 g per day, bringing the gastrointestinal absorption to account. In healthy athletes submitted daily to high-intensity strength or sprint training, the maximal oral creatine monohydrate supplementation should be of the order of two times the daily turnover, i.e., less than 5-6 g per day for less than two weeks, and the creatine monohydrate supplementation should be taken under appropriate medical supervision. The oral administration of more that 6 g per day of creatine monohydrate should be considered as a therapeutic intervention and should be prescribed by physicians only in the cases of suspected or proven deficiency, or in conditions of severe stress and/or injury. The incorporation of creatine into the medicinal product class is supported also by the use in pathological conditions, e.g., some mitochondrial cytopathies, the guanidinoacetate methyltransferase deficiency, etc. Department of Physiological-Pharmacological Sciences, Faculty of Science, University of Pavia, Italy.

  Berg EP and Allee GL (2001). Creatine monohydrate supplemented in swine finishing diets and fresh pork quality: I. A controlled laboratory experiment. J Anim Sci. 79 (12): 3075-80. Summary: Creatine monohydrate (CMH) was fed during the final stage of growth to determine its effects on fresh pork quality. Twenty-four Duroc-sired market hogs (107 kg) were individually penned and fed a corn-soybean finishing diet containing 0.55% lysine with 2% added choice white grease. Treatments consisted of a control diet (control) tested against two durations of CMH-supplemented diets (25 g CMH x pig(-1) x d(-1)) fed for 5 (5 d) or 10 (10 d) d before slaughter. Eight pigs were used per treatment. Pigs were slaughtered on day 11 of treatment (118 kg). Postmortem pH was measured in the loin (10th rib) and ham semimembranosus at 45 min (pH1) and 24 h (pH2). At 24 h, Hunter L* values were taken at the 10th rib and the ham semimembranosus. At 48 h, drip loss was determined from the loin (8th rib) and semimembranosus. Percentage of moisture, crude fat, and crude protein were determined for loin (9th rib) and semimembranosus. Treatment 2 semimembranosus tended to have a higher pH1 (P = 0.083) and pH2 (P = 0.05) than controls. Although not statistically different, 10 d semimembranosus had the highest proportion of moisture and lowest CP:moisture ratio, suggesting greater myofiber hydration. No statistical differences were detected across treatments for loin pH1, pH2, CP:moisture, or drip loss. Loins and semimembranosus from 5 d pigs had a numerically higher proportion of chemically determined i.m. fat, suggesting optimal intramuscular creatine phosphate saturation may allow for more energy to be stored as i.m. fat. Standard deviations of ham L* value means for 5 d (SD = 2.53) and 10 d (SD = 2.05) were 26 and 48% lower than controls (SD = 3.95). Standard deviations of loin L* value for 5 d (SD = 2.53) and 10 d (SD = 2.53) were 51 and 64% lower than controls (SD = 1.86). These results suggest that CMH supplementation buffers early postmortem and ultimate pH decline in the semimembranosus, which may reduce 48-h moisture loss. Department of Animal Science, University of Missouri, Columbia 65211, USA. BergEP@missouri.edu.

  Bermon S, Venembre P, Sachet C, Valour S and Dolisi C (1998). Effects of creatine monohydrate ingestion in sedentary and weight-trained older adults. Acta Physiol Scand. 164 (2): 147-55. Summary: To investigate the effects of an oral creatine supplementation in older adults, 32 elderly subjects (67-80 years; 16 females, 16 males) were randomly assigned to four equivalent subgroups (control-creatine; control-placebo; trained-creatine; trained-placebo) based on whether or not they took part in an 8-week strength training programme and an 8-week oral creatine monohydrate creatine supplementation programme. The strength training programme consisted of three sets of eight repetitions at 80% of one-repetition maximum, for leg press, leg extension and chest press, 3 days a week. The 52-day supplementation programme consisted of 20 g of creatine monohydrate (or glucose) and 8 g of glucose per day for the initial 5 days followed by 3 g of creatine monohydrate (or glucose), and 2 g of glucose per day. Prior to and after the training and supplementation periods, body mass, body fat, lower limb muscular volume, 1-, 12-repetitions maxima and isometric intermittent endurance tests for leg press, leg extension and chest press were determined. In all groups, no significant changes in anthropometric parameters were observed. For all movements, the increases in 1- and 12-repetitions maxima were greater (P < 0.02) in trained than control subjects. No significant interactions (supplementation/training/time) were observed for the 1-, 12-repetitions maxima, and the isometric intermittent endurance, whatever the movement considered. We conclude that oral creatine supplementation does not provide additional benefits for body composition, maximal dynamical strength, and dynamical and isometric endurances of healthy elderly subjects, whether or not it is associated with an effective strength training. Department of Physiology, Medical School, University of Nice-Sophia Antipolis, France.

  Bianchi MC, Tosetti M, Fornai F, Alessandri MG, Cipriani P, De Vito G and Canapicchi R (2000). Reversible brain creatine deficiency in two sisters with normal blood creatine level. Ann Neurol. 47 (4): 511-3. Summary: We describe a new creatine metabolism disorder in 2 young sisters who suffered from mental retardation and severe language delay. Blood examination, investigation of the most common neurometabolic disorders, and brain magnetic resonance imaging were normal. Diagnosis was established only by means of in vivo proton magnetic resonance spectroscopy, which disclosed generalized depletion of creatine in the brain. Creatine monohydrate oral administration led to almost complete brain creatine level restoration along with improvement of the patients' disabilities. Neuroradiology Department, S Chiara Hospital, Pisa, Italy.

  Bosco C, Tihanyi J, Pucspk J, Kovacs I, Gabossy A, Colli R, Pulvirenti G, Tranquilli C, Foti C, Viru M and Viru A (1997). Effect of oral creatine supplementation on jumping and running performance. Int J Sports Med. 18 (5): 369-72. Summary: The study was designed to investigate the effect of creatine monohydrate ingestion (20 g daily for 5 days) on performance in 45 s maximal continuous jumping and in all-out treadmill running at 20 km x h(-1), (inclination 5 degrees, duration approximately 60s). The participants were qualified sprinters and jumpers. The effect of creatine was compared with placebo in a double-blind design. Creatine (Cr) supplementation led to a significant enhancement of performance capacity in the jumping test by 7% during the first 15 s and by 12% during the second 15 s of the exercise. The positive effect of Cr supplementation was not observed in the last third of the continuous jumping exercise, when the contribution of anaerobic metabolism was decreasing. The time of intensive running up to exhaustion improved by 13%. The results show that Cr supplementation helps to prolong the time during which the maximal rate of power output could be maintained. University of Rome-Tor Vergata, Fondazione Don Gnocchi, Italy.

  Burke DG, Chilibeck PD, Davidson KS, Candow DG, Farthing J and Smith-Palmer T (2001). The effect of whey protein supplementation with and without creatine monohydrate combined with resistance training on lean tissue mass and muscle strength. Int J Sport Nutr Exerc Metab. 11 (3): 349-64. Summary: Our purpose was to assess muscular adaptations during 6 weeks of resistance training in 36 males randomly assigned to supplementation with whey protein (W; 1.2 g/kg/day), whey protein and creatine monohydrate (WC; 0.1 g/kg/day), or placebo (P; 1.2 g/kg/day maltodextrin). Measures included lean tissue mass by dual energy x-ray absorptiometry, bench press and squat strength (1-repetition maximum), and knee extension/flexion peak torque. Lean tissue mass increased to a greater extent with training in WC compared to the other groups, and in the W compared to the P group (p < .05). Bench press strength increased to a greater extent for WC compared to W and P (p < .05). Knee extension peak torque increased with training for WC and W (p < .05), but not for P. All other measures increased to a similar extent across groups. Continued training without supplementation for an additional 6 weeks resulted in maintenance of strength and lean tissue mass in all groups. Males that supplemented with whey protein while resistance training demonstrated greater improvement in knee extension peak torque and lean tissue mass than males engaged in training alone. Males that supplemented with a combination of whey protein and creatine had greater increases in lean tissue mass and bench press than those who supplemented with only whey protein or placebo. However, not all strength measures were improved with supplementation, since subjects who supplemented with creatine and/or whey protein had similar increases in squat strength and knee flexion peak torque compared to subjects who received placebo. Department of Human Kinetics, St. Francis Xavier University, Antigonish, Nova Scotia, B2G 2W5, Canada.

  Cacic M, Wilichowski E, Mejaski-Bosnjak V, Fumic K, Lujic L, Marusic Della Marina B and Hanefeld F (2001). Cytochrome c oxidase partial deficiency-associated Leigh disease presenting as an extrapyramidal syndrome. J Child Neurol. 16 (8): 616-9. Summary: Leigh disease is a subacute neurodegenerative disorder characterized by symmetric necrotic lesions in the basal ganglia, cerebellum, thalamus, brain stem, and optical nerves and caused by altered oxidative phosphorylation. We describe the clinical, biochemical, neuroimaging, and molecular studies of a 19-year-old boy with early-onset Leigh disease manifesting as severe extrapyramidal disorder with generalized dystonia and choreoathetosis. He was born of healthy parents after an uneventful pregnancy and delivery. At the age of 2 1/2 years, after a minor respiratory infection, he developed unstable, broad-based gait and tremor of the hands. These symptoms persisted for the next several years, when ataxia became more prominent. Difficulty in swallowing, dysarthria, trunk dystonia, and marked dyskinesia of the arms and hands gradually developed. Nystagmus, transient ptosis, and strabismus also appeared. Abnormal laboratory findings included elevated plasma and cerebrospinal fluid lactate and pyruvate, with an abnormal lactate/pyruvate ratio. Cranial computed tomography and magnetic resonance imaging demonstrated signs of cerebellar atrophy, bilateral and symmetric hypodensities in the lentiform nucleus and thalamus, and transient hyperintensities of cerebral peduncles in T2-weighted sequences suggestive of Leigh disease. Muscle biopsy revealed isolated fiber atrophy, necrotic fibers undergoing phagocytosis, and no ragged-red fibers. The measured catalytic activity of cytochrome c oxidase in skeletal muscle homogenates demonstrated a partial cytochrome c oxidase deficiency No abnormalities in the mitochondrial genome and in the SURF-1 gene were found. The boy is currently receiving levodopa therapy, creatine monohydrate, and a high dosage of thiamine and lipoic acid, his condition is stabilized, and extrapyramidal symptoms are less pronounced. Department of Pediatrics, Children's Hospital Zagreb, Croatia.

  Cecil KM, Salomons GS, Ball WS, Jr., Wong B, Chuck G, Verhoeven NM, Jakobs C and DeGrauw TJ (2001). Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect? Ann Neurol. 49 (3): 401-4. Summary: Recent reports highlight the utility of in vivo magnetic resonance spectroscopy (MRS) techniques to recognize creatine deficiency syndromes affecting the central nervous system (CNS). Reported cases demonstrate partial reversibility of neurologic symptoms upon restoration of CNS creatine levels with the administration of oral creatine. We describe a patient with a brain creatine deficiency syndrome detected by proton MRS that differs from published reports. Metabolic screening revealed elevated creatine in the serum and urine, with normal levels of guanidino acetic acid. Unlike the case with other reported creatine deficiency syndromes, treatment with oral creatine monohydrate demonstrated no observable increase in brain creatine with proton MRS and no improvement in clinical symptoms. In this study, we report a novel brain creatine deficiency syndrome most likely representing a creatine transporter defect. Division of Radiology, Children's Hospital Medical Center and the University of Cincinnati, OH 45229, USA. cecil@athena.chmcc.org.

  Casey A, Constantin-Teodosiu D, Howell S, Hultman E and Greenhaff PL (1996). Creatine ingestion favorably affects performance and muscle metabolism during maximal exercise in humans. Am J Physiol. 271 (1 Pt 1): E31-7. Summary: Nine male subjects performed two bouts of 30-s maximal isokinetic cycling before and after ingestion of 20 g creatine (Cr) monohydrate/day for 5 days. Cr ingestion produced a 23.1 +/- 4.7 mmol/kg dry matter increase in the muscle total creatine (TCr) concentration. Total work production during bouts 1 and 2 increased by approximately 4%, and the cumulative increases in both peak and total work production over the two exercise bouts were positively correlated with the increase in muscle TCr. Cumulative loss of ATP was 30.7 +/- 12.2% less after Cr ingestion, despite the increase in work production. Resting phosphocreatine (PCr) increased in type I and II fibers. Changes in PCr before exercise bouts 1 and 2 in type II fibers were positively correlated with changes in PCr degradation during exercise in this fiber type and changes in total work production. The results suggest that improvements in performance were mediated via improved ATP resynthesis as a consequence of increased PCr availability in type II fibers. Department of Physiology and Pharmacology, University of Nottingham Medical School, Queen's Medical Center, United Kingdom.

  Casey A and Greenhaff PL (2000). Does dietary creatine supplementation play a role in skeletal muscle metabolism and performance? Am J Clin Nutr. 72 (2 Suppl): 607S-17S. Summary: Fatigue sustained during short-term, high-intensity exercise in humans is associated with the inability of skeletal muscle to maintain a high rate of anaerobic ATP production from phosphocreatine hydrolysis. Ingestion of creatine monohydrate at a rate of 20 g/d for 5-6 d was shown to increase the total creatine concentration of human skeletal muscle by approximately 25 mmol/kg dry mass, some 30% of this in phosphorylated form as phosphocreatine. A positive relation was then shown between muscle creatine uptake and improvements in performance during repeated bouts of maximal exercise. However, there is no evidence that increasing intake > 20-30 g/d for 5-6 d has any potentiating effect on creatine uptake or performance. In individuals in whom the initial total creatine concentration already approached 150 mmol/kg dry mass, neither creatine uptake nor an effect on phosphocreatine resynthesis or performance was found after supplementation. Loss of ATP during heavy anaerobic exercise was found to decline after creatine ingestion, despite an increase in work production. These results suggest that improvements in performance are due to parallel improvements in ATP resynthesis during exercise as a consequence of increased phosphocreatine availability. Creatine uptake is augmented by combining creatine supplementation with exercise and with carbohydrate ingestion. Centre for Human Sciences, Defence Evaluation and Research Agency, Farnborough, United Kingdom. acasey@dera.gov.uk.

  Cox G, Mujika I, Tumilty D and Burke L (2002). Acute creatine supplementation and performance during a field test simulating match play in elite female soccer players. Int J Sport Nutr Exerc Metab. 12 (1): 33-46. Summary: This study investigated the effects of acute creatine (Cr) supplementation on the performance of elite female soccer players undertaking an exercise protocol simulating match play. On two occasions, 7 days apart, 12 players performed 5 x 11-min exercise testing blocks interspersed with 1 min of rest. Each block consisted of 11 all-out 20-m running sprints, 2 agility runs, and 1 precision ball-kicking drill, separated by recovery 20-m walks,jogs, and runs. After the initial testing session, subjects were assigned to either a CREATINE (5 g of Cr, 4 times per day for 6 days) or a PLACEBO group (same dosage of a glucose polymer) using a double-blind research design. Body mass (BM) increased (61.7 +/- 8.9 to 62.5 < or = 8.9 kg, p < .01) in the CREATINE group; however, no change was observed in the PLACEBO group (63.4 < or = 2.9 kg to 63.7 +/- 2.5 kg). No overall change in 20-m sprint times and agility run times were observed, although the CREATINE group achieved faster post-supplementation times in sprints 11, 13, 14, 16, 21, 23, 25, 32, and 39 (p <.05), and agility runs 3, 5, and 8 (p < .05). The accuracy of shooting was unaffected in both groups. In conclusion, acute Cr supplementation improved performance of some repeated sprint and agility tasks simulating soccer match play, despite an increase in BM. Australian Institute of Sport, Department of Sports Nutrition, Australian Capital Territory, Belconnen.

  Dangott B, Schultz E and Mozdziak PE (2000). Dietary creatine monohydrate supplementation increases satellite cell mitotic activity during compensatory hypertrophy. Int J Sports Med. 21 (1): 13-6. Summary: Nutritional status influences muscle growth and athletic performance, but little is known about the effect of nutritional supplements, such as creatine, on satellite cell mitotic activity. The purpose of this study was to examine the effect of oral creatine supplementation on muscle growth, compensatory hypertrophy, and satellite cell mitotic activity. Compensatory hypertrophy was induced in the rat plantaris muscle by removing the soleus and gastrocnemius muscles. Immediately following surgery, a group of six rats was provided with elevated levels of creatine monohydrate in their diet. Another group of six rats was maintained as a non-supplemented control group. Twelve days following surgery, all rats were implanted with mini-osmotic pumps containing the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) to label mitotically active satellite cells. Four weeks after the initial surgery the rats were killed, plantaris muscles were removed and weighed. Subsequently, BrdU-labeled and non-BrdU-labeled nuclei were identified on enzymatically isolated myofiber segments. Muscle mass and myofiber diameters were larger (P < 0.05) in the muscles that underwent compensatory hypertrophy compared to the control muscles, but there were no differences between muscles from creatine-supplemented and non-creatine-supplemented rats. Similarly, compensatory hypertrophy resulted in an increased (P < 0.05) number of BrdU-labeled myofiber nuclei, but creatine supplementation in combination with compensatory hypertrophy resulted in a higher (P < 0.05) number of BrdU-labeled myofiber nuclei compared to compensatory hypertrophy without creatine supplementation. Thus, creatine supplementation in combination with an increased functional load results in increased satellite cell mitotic activity. Department of Anatomy, University of Wisconsin-Medical School, Madison, USA.

  Dechent P, Pouwels PJ, Wilken B, Hanefeld F and Frahm J (1999). Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol. 277 (3 Pt 2): R698-704. Summary: The effect of oral creatine supplementation on brain metabolite concentrations was investigated in gray matter, white matter, cerebellum, and thalamus of healthy young volunteers by means of quantitative localized proton magnetic resonance spectroscopy in vivo (2.0 T, stimulated echo acquisition mode sequence; repetition time = 6,000 ms, echo time = 20 ms, middle interval = 10 ms, automated spectral evaluation). Oral consumption of 4 x 5 g creatine-monohydrate/day for 4 wk yielded a statistically significant increase (8.7% corresponding to 0.6 mM, P < 0.001) of the mean concentration of total creatine (tCr) when averaged across brain regions and subjects (n = 6). The data revealed considerable intersubject variability (3.5-13.3%), with the smallest increases observed for the two male volunteers with the largest body weights. A regional analysis resulted in significant increases of tCr in gray matter (4.7%), white matter (11.5%), and cerebellum (5.4%) and was most pronounced in thalamus (14.6% corresponding to 1.0 mM). Other findings were significant decreases of N-acetyl-containing compounds in cerebellum and thalamus as well as of choline-containing compounds in thalamus. All cerebral metabolic alterations caused by oral Cr were reversible, as evidenced by control measurements at least 3 mo after the diet. This work demonstrates that excess consumption of Cr yields regionally dependent increases of the tCr concentration in human brain over periods of several weeks. Biomedizinische NMR Forschungs GmbH am Max-Planck-Institut fur Biophysikalische Chemie, D-37070, Georg-August-Universitat, D-37075 Gottingen, Germany.

  Demant TW and Rhodes EC (1999). Effects of creatine supplementation on exercise performance. Sports Med. 28 (1): 49-60. Summary: While creatine has been known to man since 1835, when a French scientist reported finding this constitutent of meat, its presence in athletics as a performance enhancer is relatively new. Amid claims of increased power and strength, decreased performance time and increased muscle mass, creatine is being hailed as a true ergogenic aid. Creatinine is synthesised from the amino acids glycine, arginine and methionine in the kidneys, liver and pancreas, and is predominantly found in skeletal muscle, where it exists in 2 forms. Approximately 40% is in the free creatine form (Crfree), while the remaining 60% is in the phosphorylated form, creatine phosphate (CP). The daily turnover rate of approximately 2 g per day is equally met via exogenous intake and endogenous synthesis. Although creatine concentration (Cr) is greater in fast twitch muscle fibres, slow twitch fibres have a greater resynthesis capability due to their increased aerobic capacity. There appears to be no significant difference between males and females in Cr, and training does not appear to effect Cr. The 4 roles in which creatine is involved during performance are temporal energy buffering, spatial energy buffering, proton buffering and glycolysis regulation. Creatine supplementation of 20 g per day for at least 3 days has resulted in significant increases in total Cr for some individuals but not others, suggesting that there are 'responders' and 'nonresponders'. These increases in total concentration among responders is greatest in individuals who have the lowest initial total Cr, such as vegetarians. Increased concentrations of both Crfree and CP are believed to aid performance by providing more short term energy, as well as increase the rate of resynthesis during rest intervals. Creatine supplementation does not appear to aid endurance and incremental type exercises, and may even be detrimental. Studies investigating the effects of creatine supplementation on short term, high intensity exercises have reported equivocal results, with approximately equal numbers reporting significant and nonsignificant results. The only side effect associated with creatine supplementation appears to be a small increase in body mass, which is due to either water retention or increased protein synthesis. School of Human Kinetics, University of British Columbia, Vancouver, Canada.

  Dupont-Versteegden EE, Houle JD, Gurley CM and Peterson CA (1998). Early changes in muscle fiber size and gene expression in response to spinal cord transection and exercise. Am J Physiol. 275 (4 Pt 1): C1124-33. Summary: Muscles of spinal cord-transected rats exhibit severe atrophy and a shift toward a faster phenotype. Exercise can partially prevent these changes. The goal of this study was to investigate early events involved in regulating the muscle response to spinal transection and passive hindlimb exercise. Adult female Sprague-Dawley rats were anesthetized, and a complete spinal cord transection lesion (T10) was created in all rats except controls. Rats were killed 5 or 10 days after transection or they were exercised daily on motor-driven bicycles starting at 5 days after transection and were killed 0.5, 1, or 5 days after the first bout of exercise. Structural and biochemical features of soleus and extensor digitorum longus (EDL) muscles were studied. Atrophy was decreased in all fiber types of soleus and in type 2a and type 2x fibers of EDL after 5 days of exercise. However, exercise did not appear to affect fiber type that was altered within 5 days of spinal cord transection: fibers expressing myosin heavy chain 2x increased in soleus and EDL, and extensive coexpression of myosin heavy chain in soleus was apparent. Activation of satellite cells was observed in both muscles of transected rats regardless of exercise status, evidenced by increased accumulation of MyoD and myogenin. Increased expression was transient, except for MyoD, which remained elevated in soleus. MyoD and myogenin were detected both in myofiber and in satellite cell nuclei in both muscles, but in soleus, MyoD was preferentially expressed in satellite cell nuclei, and in EDL, MyoD was more readily detectable in myofiber nuclei, suggesting that MyoD and myogenin have different functions in different muscles. Exercise did not affect the level or localization of MyoD and myogenin expression. Similarly, Id-1 expression was transiently increased in soleus and EDL upon spinal cord transection, and no effect of exercise was observed. These results indicate that passive exercise can ameliorate muscle atrophy after spinal cord transection and that satellite cell activation may play a role in muscle plasticity in response to spinal cord transection and exercise. Finally, the mechanisms underlying maintenance of muscle mass are likely distinct from those controlling myosin heavy chain expression. Department of Geriatrics, University of Arkansas for Medical Sciences, Geriatric Research, Education, Clinical Center, McClellan Department of Veterans Affairs Hospital, Little Rock, Arkansas 72205, USA.

  Earnest CP, Almada AL and Mitchell TL (1996). High-performance capillary electrophoresis-pure creatine monohydrate reduces blood lipids in men and women. Clin Sci (Lond). 91 (1): 113-8. Summary: 1. A randomized, double-blind, placebo-controlled trial utilizing creatine as a potential lipid-lowering agent was conducted to determine plasma lipid, lipoprotein, glucose, urea nitrogen and creatinine profiles in men and women ranging in age from 32 to 70 years. 2. Thirty-four subjects (18 men and 16 women) with total cholesterol concentrations exceeding 200 mg/dl received either a creatine supplement (5 g of creatine plus 1 g of glucose) or a glucose placebo (6 g of glucose) for 56 days. Creatine and placebo were taken orally four times a day for 5 days and then twice a day for 51 days. Plasma analyses were measured at baseline, 4 and 8 weeks of treatment, and at 4 weeks after cessation of treatment (week 12). 3. Significant reductions in plasma total cholesterol, triacylglycerols and very-low-density lipoprotein-C occurred within the creatine monohydrate group. Minor reductions in plasma total cholesterol from baseline (233 +/- 9 mg/dl) of 6% and 5% occurred at weeks 4 and 8, respectively, before returning to baseline at week 12. Baseline triacylglycerols (194 +/- 21 mg/dl) and very-low-density lipoprotein-C (39 +/- 4 mg/dl) were reduced by 23% and 22% at weeks 4 and 8, respectively, and remained attenuated by 26% at week 12. These results remained consistent when data were separated and analysed by gender. Finally, a small, but statistically significant increase in urea nitrogen was observed in women between baseline (11.8 +/- 0.7 mg/dl) and week 8 (13.8 +/- 0.7 mg/dl, P < 0.05). No significant differences were noted for low-density lipoprotein-C, high-density lipoprotein-C, total cholesterol/high-density lipoprotein ratio, glucose, creatinine, body mass, body mass index or physical activity within or between the experimental and placebo groups. However, a trend towards reduced blood glucose levels was present in males given creatine monohydrate (P = 0.051). 4. These preliminary data suggest that creatine monohydrate may modulate lipid metabolism in certain individuals. These observations may demonstrate practical efficacy to the hyperlipidaemic patient as well as providing possible new mechanistic insights into the cellular regulation of blood lipid concentrations. Texas Woman's University, Denton, USA.

  Febbraio MA, Flanagan TR, Snow RJ, Zhao S and Carey MF (1995). Effect of creatine supplementation on intramuscular TCr, metabolism and performance during intermittent, supramaximal exercise in humans. Acta Physiol Scand. 155 (4): 387-95. Summary: This study examined the effect of (a) creatine supplementation on exercise metabolism and performance and (b) changes in intramuscular total creatine stores following a 5 day supplementation period and a 28 day wash-out period. Six men performed four exercise trials, each consisting of four 1 min cycling bouts, punctuated by 1 min of rest followed by a fifth bout to fatigue, all at a workload estimated to require 115 or 125% VO2,max. After three familiarization trials, one trial was conducted following a creatine monohydrate supplementation protocol (CREAT); the other after 28 d without creatine supplementation, in which the last 5 d involved placebo ingestion (CON). Intramuscular TCr was elevated (P < 0.05) in CREAT compared with the final familiarization trial (FAM 3) and CON. Concentrations of this metabolite in these latter trials were not different. In addition, a main effect (P < 0.05) for treatment was observed for PCr when the data from CREAT were compared with CON. In contrast, no differences were observed in the total adenine nucleotide pool (ATP+ADP+AMP), inosine 5'-monophosphate, ammonia, lactate or glycogen when comparing CREAT with CON. Despite the differences in TCr and PCr concentrations when comparing CREAT with other trials, no difference was observed in exercise duration in the fifth work bout. These data demonstrate that creatine supplementation results in an increase in TCr but this has no effect on performance during exercise of this nature, where the creatine kinase system is not the principal energy supplier. In addition 28 d without supplementation is a sufficient time to return intramuscular TCr stores to basal levels. Department of Human Movement Science, Royal Melbourne Institute of Technology, Bundoora, Australia.

  Green JM, McLester JR, Smith JE and Mansfield ER (2001). The effects of creatine supplementation on repeated upper- and lower-body Wingate performance. J Strength Cond Res. 15 (1): 36-41. Summary: Nineteen physically active men supplemented their diet with 20 g per day creatine monohydrate (Cr group) or placebo (PI group) for 6 days. Before and after supplementation, subjects performed 3 arm Wingates (AW1, AW2, and AW3) and 3 leg Wingates (LW1, LW2, and LW3) on consecutive days. Wingates were separated by 2 minutes each. Mean power (MP), peak power (PP), and percent decrease (%D) were compared between and within groups. MP did not change significantly for arms or legs. PP did not change significantly for legs. PP increased significantly in the Cr group (AW1) and for the P1 group (AW1 and AW3). MP and PP were not significantly different between groups. The %D increased significantly in the P1 group (AW1, AW3, and LW3). For the Cr group, %D decreased significantly (pre vs. post) and was significantly lower than for the P1 group (LW2-post). Results suggest that short-term Cr supplementation does not enhance MP and PP during repeated upper- and lower-body Wingate tests when not accompanied by an increase in body weight. However, changes in %D suggest possible ergogenic effects. Dept of Physical Education and Recreation, Western Kentucky University, Bowling Green 42101, USA. 

  Grindstaff PD, Kreider R, Bishop R, Wilson M, Wood L, Alexander C and Almada A (1997). Effects of creatine supplementation on repetitive sprint performance and body composition in competitive swimmers. Int J Sport Nutr. 7 (4): 330-46. Summary: In a double-blind and randomized manner, 18 male and female junior competitive swimmers supplemented their diets with 21 g.day-1 of creatine monohydrate (Cr) or a maltodextrin placebo (P) for 9 days during training. Prior to and following supplementation, subjects performed three 100-m freestyle sprint swims (long course) with 60 s rest/recovery between heats. In addition, subjects performed three 20-s arm ergometer maximal-effort sprint tests in the prone position with 60 s rest/recovery between sprint tests. Significant differences were observed among swim times, with Cr subjects swimming significantly faster than P subjects following supplementation in Heat 1 and significantly decreasing swim time in the second 100-m sprint. There was also some evidence that cumulative time to perform the three 100-m swims was decreased in the Cr group. Results indicate that 9 days of Cr supplementation during swim training may provide some ergogenic value to competitive junior swimmers during repetitive sprint performance. Department of Human Movement Sciences and Education, University of Memphis, Memphis, TN 38152, USA.

  Guzik AC, Southern LL, Matthews JO, Bidner TD and Ladner JP (2000). Ornithine alpha-ketoglutarate and creatine effects on growth and plasma metabolites of nursery pigs. J Anim Sci. 78 (4): 1022-8. Summary: Four experiments were conducted to determine the effect of dietary ornithine alpha-ketoglutarate (OKG) and creatine monohydrate on growth performance and plasma metabolites of nursery pigs. In each experiment, treatments were replicated with four to five pens of four to six pigs each. Each experiment lasted from 3 to 4 wk and Phase I (1.6% Lys) and Phase II (1.3 to 1.5% Lys) diets were fed for 9 to 16 d each. In Exp. 1, pigs (4.7 kg and 15 d of age) were fed diets containing 0, .10, or .75% OKG. Daily gain during a 13-d Phase I period and ADFI during Phase I and overall (29 d) were increased (P < .10) in pigs fed .75% OKG. Gain:feed ratio was not affected (P > .10) by diet. In Exp. 2, pigs (7.1 kg and 23 d of age) were fed 0 or .50% OKG during Phase I only. During Phase I, II, and overall, ADG and ADFI were not affected (P > .10) by OKG supplementation, but gain:feed was decreased during Phase I (P < .04), Phase II (P < .08), and overall (P < .04). Plasma urea N (PUN), glucose, and NEFA concentrations were not affected (P > .10) by OKG supplementation in this experiment. In Exp. 3, pigs (5.8 kg and 20 d of age) were fed diets containing 0, .10, or .50% creatine. Creatine tended to linearly decrease ADG (P = .11) and plasma albumin (P = .12) and PUN (P < .10) concentrations in Phase II (d 12 to 26). In Exp. 4, 850 mg of OKG or 750 mg of creatine was provided daily by oral capsule to pigs 4 d before weaning to 2 d after weaning. Pigs within a litter received either no capsule or capsules containing OKG or creatine. After weaning, pigs that received no capsule before weaning received no treatment, .50% creatine, or .50% OKG in the nursery diet. Pigs that received OKG before weaning received no treatment or .50% OKG, and pigs that received creatine before weaning received no treatment or .50% creatine in the nursery diet. Pigs weighed 3.9 kg 4 d before weaning and 4.9 kg at weaning at an average age of 20 d. The OKG provided by capsule decreased ADG (P < .02) and ADFI (P < .09) during Phase II. The OKG did not affect (P > .10) plasma NEFA, glucose, or urea N concentrations. Creatine added to the nursery diet increased (P < .02) ADFI and decreased (P < .10) gain:feed during Phase II and overall. Creatine in the nursery diet also increased (P < .01) PUN, but it did not affect plasma glucose or NEFA concentrations. Creatine and OKG have variable effects on growth performance and plasma metabolites of nursery pigs. Department of Animal Science, Louisiana State University Agricultural Center, Baton Rouge 70803, USA.

  Hamilton KL, Meyers MC, Skelly WA and Marley RJ (2000). Oral creatine supplementation and upper extremity anaerobic response in females. Int J Sport Nutr Exerc Metab. 10 (3): 277-89. Summary: The purpose of this study was to investigate the influence of creatine monohydrate (CrH2O) on upper extremity anaerobic response in strength-trained females involved in overhand sports. Two movements were utilized in this evaluation: elbow flexion (EF) and shoulder internal rotation (IR). Subjects were pair-matched and assigned to receive placebo (n = 13) or 25 g CrH2O (n = 11) for 7 days. Pre- and post-treatment measurements included peak concentric and eccentric isokinetic torque, isotonic 1RM, and fatigue (FAT) during EF; isotonic 1RM, FAT, and peak velocity during IR; and body weight. MANOVAs revealed significant interaction between treatment and trial for EF (p <.05) but not for IR or weight. Univariate analysis indicated a significantly greater change in EFFAT following CrH2O than following placebo. Thus, CrH2O did not influence peak EF or IR strength, IR work to fatigue, or IR velocity, but was associated with greater work capacity during fatiguing EF. These data suggest that CrH2O may enhance upper extremity work capacity, but this enhancement may not extend to the muscles primarily responsible for overhand sports performance. Department of Health and Human Development, Montana State University; Baylor College of Medicine, Houston, TX 77030, USA.

  Harris RC, Nevill M, Harris DB, Fallowfield JL, Bogdanis GC and Wise JA (2002). Absorption of creatine supplied as a drink, in meat or in solid form. J Sports Sci. 20 (2): 147-51. Summary: We examined the plasma concentration curve obtained over 6 h after the ingestion of 2 g of creatine (Cr) (equivalent to 2.3 g Cr x H2O) contained in meat or in solution in five non-users of creatine supplements. Peak plasma creatine concentration was lower after the ingestion of meat but was maintained close to this for a longer period. Measurements of the area under the plasma concentration curve indicated approximate bioequivalence of creatine contained in meat with the same dose supplied in a solution. In a separate study, we examined the plasma concentration time curve after ingestion of solid Cr x H2O. Creatine ingested as a lozenge (crushed in the mouth and swallowed) or as a crystalline suspension in ice cold water resulted in a 20% lower peak concentration and 30-35% smaller area under the plasma creatine concentration curve than the same dose administered in solution. Despite a possibly lower bioavailability, 2.3 g Cr x H2O supplied in either solid form was nonetheless sufficient to raise the plasma concentration five- to six-fold in individuals with a mean body mass of 75.6 kg. We conclude that creatine administered as meat or in solid form is readily absorbed but may result in slightly lower peak concentrations than when the same dose is ingested as a solution. Exercise Physiology Research Group, University College Chichester, UK. rharris@ucc.ac.uk.

  Harris RC, Soderlund K and Hultman E (1992). Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond). 83 (3): 367-74. Summary: 1. The present study was undertaken to test whether creatine given as a supplement to normal subjects was absorbed, and if continued resulted in an increase in the total creatine pool in muscle. An additional effect of exercise upon uptake into muscle was also investigated. 2. Low doses (1g of creatine monohydrate or less in water) produced only a modest rise in the plasma creatine concentration, whereas 5g resulted in a mean peak after 1h of 795 (SD 104) mumol/l in three subjects weighing 76-87 kg. Repeated dosing with 5g every 2h sustained the plasma concentration at around 1000 mumol/l. A single 5g dose corresponds to the creatine content of 1.1 kg of fresh, uncooked steak. 3. Supplementation with 5g of creatine monohydrate, four or six times a day for 2 or more days resulted in a significant increase in the total creatine content of the quadriceps femoris muscle measured in 17 subjects. This was greatest in subjects with a low initial total creatine content and the effect was to raise the content in these subjects closer to the upper limit of the normal range. In some the increase was as much as 50%. 4. Uptake into muscle was greatest during the first 2 days of supplementation accounting for 32% of the dose administered in three subjects receiving 6 x 5g of creatine monohydrate/day. In these subjects renal excretion was 40, 61 and 68% of the creatine dose over the first 3 days. Approximately 20% or more of the creatine taken up was measured as phosphocreatine. No changes were apparent in the muscle ATP content.(ABSTRACT TRUNCATED AT 250 WORDS). Department of Clinical Chemistry II, Karolinska Institute, Huddinge University Hospital, Sweden.

  Hespel P, Op't Eijnde B, Van Leemputte M, Urso B, Greenhaff PL, Labarque V, Dymarkowski S, Van Hecke P and Richter EA (2001). Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans. J Physiol. 536 (Pt 2): 625-33. Summary: 1. We investigated the effect of oral creatine supplementation during leg immobilization and rehabilitation on muscle volume and function, and on myogenic transcription factor expression in human subjects. 2. A double-blind trial was performed in young healthy volunteers (n = 22). A cast was used to immobilize the right leg for 2 weeks. Thereafter the subjects participated in a knee-extension rehabilitation programme (3 sessions x week(-1), 10 weeks). Half of the subjects received creatine monohydrate (CR; from 20 g down to 5 g daily), whilst the others ingested placebo (P; maltodextrin). 3. Before and after immobilization, and after 3 and 10 weeks of rehabilitation training, the cross-sectional area (CSA) of the quadriceps muscle was assessed by NMR imaging. In addition, an isokinetic dynamometer was used to measure maximal knee-extension power (Wmax), and needle biopsy samples taken from the vastus lateralis muscle were examined to asses expression of the myogenic transcription factors MyoD, myogenin, Myf5, and MRF4, and muscle fibre diameters. 4. Immobilization decreased quadriceps muscle CSA (approximately 10 %) and Wmax (approximately 25 %) by the same magnitude in both groups. During rehabilitation, CSA and Wmax recovered at a faster rate in CR than in P (P < 0.05 for both parameters). Immobilization changed myogenic factor protein expression in neither P nor CR. However, after rehabilitation myogenin protein expression was increased in P but not in CR (P < 0.05), whilst MRF4 protein expression was increased in CR but not in P (P < 0.05). In addition, the change in MRF4 expression was correlated with the change in mean muscle fibre diameter (r = 0.73, P < 0.05). 5. It is concluded that oral creatine supplementation stimulates muscle hypertrophy during rehabilitative strength training. This effect may be mediated by a creatine-induced change in MRF4 and myogenin expression. Faculty of Physical Education and Physiotherapy, Exercise Physiology and Biomechanics Laboratory, Department of Kinesiology, Faculty of Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.

  Ikeda K, Iwasaki Y and Kinoshita M (2000). Oral administration of creatine monohydrate retards progression of motor neuron disease in the wobbler mouse. Amyotroph Lateral Scler Other Motor Neuron Disord. 1 (3): 207-12. Summary: BACKGROUND AND AIMS: Creatine has a neuroprotective effect in mutant superoxide dismutase (G93A) transgenic mice, an animal model of motor neuron disease (MND). Treatment with creatine monohydrate enhances muscle strength in patients with neuromuscular disorders. The purpose of our study was to determine whether administration of creatine monohydrate can attenuate progressive disease in wobbler mice. METHODS: After an initial diagnosis of disease at the age of 3-4 weeks, creatine monohydrate (5 or 50 mg/kg, po) or vehicle was given to wobbler mice daily for 4 weeks in a blinded fashion. We compared symptomatic and neuropathological assessments among the three groups. RESULTS: Creatine levels in biceps muscles were increased by approximately 20% following administration of higher-dose creatine monohydrate. In comparison with vehicle, treatment with higher doses of creatine monohydrate potentiated grip strength, attenuated forelimb contracture and increased the weight of biceps muscles. Mice treated with higher doses of creatine monohydrate showed retarded denervation muscle atrophy in the biceps muscles and reduced degeneration of the spinal motor neurons. Thus, oral administration of creatine monohydrate delayed the progression of disease in wobbler mice. CONCLUSION: Our results indicate that this molecule may have therapeutic potential in human motor neuropathy or MND. Fourth Department of Internal Medicine, Toho University, Ohashi Hospital, Tokyo, Japan.

  Ipsiroglu OS, Stromberger C, Ilas J, Hoger H, Muhl A and Stockler-Ipsiroglu S (2001). Changes of tissue creatine concentrations upon oral supplementation of creatine-monohydrate in various animal species. Life Sci. 69 (15): 1805-15. Summary: Creatine is a nutritional supplement with major application as ergogenic and neuroprotective substrate. Varying supplementation protocols differing in dosage and duration have been applied but systematic studies of total creatine (creatine and phosphocreatine) content in the various organs of interest are lacking. We investigated changes of total creatine concentrations in brain, muscle, heart, kidney, liver, lung and venous/portal plasma of guinea pigs, mice and rats in response to 2-8 weeks oral creatine-monohydrate supplementation (1.3-2 g/kg/d; 1.4-2.8% of dietary intake). Analysis of creatine and phosphocreatine content was performed by high performance liquid chromatography. Total creatine was determined as the sum of creatine and phosphocreatine. Presupplementation total creatine concentrations were high in brain, skeletal and heart muscle (10-22 micromol/g wet weight), and low in liver, kidney and lung (5-8 micromol/g wet weight). During creatine supplementation, the relative increase of total creatine was low (15-55% of presupplementation values) in organs with high presupplementation concentrations, and high (260-500% of presupplementation values) in organs with low presupplementation concentrations. The increase of total creatine concentrations was most pronounced after 4 weeks of supplementation. In muscle, brain, kidney and lungs, an additional increase (p<0.01) was observed between 2-4 and 2-8 weeks of supplementation. Absolute concentrations of phosphocreatine increased, but there was no increase of the relative (percentual) proportion of phosphocreatine (14-45%) during supplementation. Statistical comparison of total creatine concentrations across the species revealed no systematically differences in organ distribution and in time points of supplementation. Results suggest that in organs with low presupplementation creatine levels (liver, kidney), a major determinant of creatine uptake is an extra-intracellular concentration gradient. In organs with high presupplementation total creatine levels like brain, skeletal and heart muscle, the maximum capacity of creatine accumulation is low compared to other organs. A supplementation period of 2 to 4 weeks is necessary for significant augmentation of the creatine pool in these organs. Department of Neonatology and General Pediatrics, University Hospital of Vienna, Austria.

  Jacobs PL, Mahoney ET, Cohn KA, Sheradsky LF and Green BA (2002). Oral creatine supplementation enhances upper extremity work capacity in persons with cervical-level spinal cord injury. Arch Phys Med Rehabil. 83 (1): 19-23. Summary: OBJECTIVE: To examine the effects of short-term creatine monohydrate supplementation on the upper extremity work capacity of persons with cervical-level spinal cord injury (SCI). DESIGN: Randomized, double-blind, placebo-controlled, crossover design study. Consists of 2 treatment phases lasting for 7 days, separated by a 21-day washout period. SETTING: University research laboratory trial. PARTICIPANTS: Sixteen men with complete cervical-level SCI (C5-7). INTERVENTION: Subjects were randomly assigned to 1 of 2 groups and received either 20g/d of creatine monohydrate supplement powder or placebo maltodextrin powder for the first treatment phase; the treatment was reversed in the second phase. Incremental peak arm ergometry tests, using 2-minute work stages and 1-minute recovery periods, were performed immediately before and after each treatment phase (total of 4 assessments). The initial stage was performed unloaded, with power output progressively increased 10 watts/stage until subjects had achieved volitional exhaustion. MAIN OUTCOME MEASURES: Peak power output, time to fatigue, heart rate, and metabolic measurements, including oxygen uptake (VO2), minute ventilation, tidal volume (VT), and respiration frequency. RESULTS: Significantly greater values of VO2, VCO2, and VT at peak effort after creatine supplementation (P <.001). CONCLUSIONS: Creatine supplementation enhances the exercise capacity in persons with complete cervical-level SCI and may promote greater exercise training benefits. Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL 33136, USA.

  Jacobs I (1999). Dietary creatine monohydrate supplementation. Can J Appl Physiol. 24 (6): 503-14. Summary: This paper summarizes and interprets the research published about physiological aspects of dietary supplementation with creatine monohydrate and the effects on physical performance. A nitrogenous molecule that occurs naturally in the flesh consumed by meat-eaters, creatine is also synthesized endogenously and is stored primarily in skeletal muscle. The research literature in which direct measurements of muscle creatine content have been reported indicates that most, but not all, subjects respond to "creatine loading" by increasing the total intramuscular concentration of creatine, including the concentration of phosphocreatine. The factors that affect muscle creatine stores are reviewed, as are the widely ranging results on physical performance. The mechanism of action by which increased intramuscular creatine could enhance performance is not yet clear. Original speculation was that increased phosphocreatine levels prior to commencing exercise, in conjunction with higher free creatine concentration, would prolong the time required until performance-limiting levels of phosphocreatine were reached during intense exercise. It was also speculated that restoration of phosphocreatine levels between bouts of such exercise would be more rapid. More recent studies question such speculation. This review includes a discussion of what is known about the health risks and side-effects associated with creatine loading. The paper concludes with speculation about the unprecedented attention given to creatine supplementation by recreational and competitive athletes and the media. Defence and Civil Institute of Environmental Medicine, Toronto, Ontario.

  Jacobs I, Bleue S and Goodman J (1997). Creatine ingestion increases anaerobic capacity and maximum accumulated oxygen deficit. Can J Appl Physiol. 22 (3): 231-43. Summary: The purpose of this study was to test the hypothesis that ingestion of creatine monohydrate increases anaerobic exercise capacity, as reflected by the maximal accumulated oxygen deficit (MAOD). Subjects were assigned, double-blind, to placebo (PL, n = 12) or creatine (CR, n = 14) groups and ingested 5-g doses 4 times daily of artificial sweetener or artificially sweetened creatine monohydrate, respectively, for 5 days. On a separate day subjects exercised to exhaustion at 125% VO2max. After two familiarization trials, MAOD was again determined before treatment, after 5 days of PL or CR treatment, and 7 days later. MAOD increased after CR treatment from 4.04 +/- 0.31 to 4.41 +/- 0.34 L (p < .001) and remained elevated for another 7 days (4.31 +/- 0.33, p < .001). Time to exhaustion also increased in CR from 130 +/- 7 to 141 +/- 7 s (p < .01) and remained increased for another 7 days (139 +/- 8 s, p < .01). These data demonstrate that ingesting creatine monohydrate for 5 days increases the MAOD, and is likely to have an ergogenic effect on supramaximal exercise performance that persists for at least a week after treatment. Defence and Civil Institute of Environmental Medicine, North York, ON.

  Javierre C, Lizarraga MA, Ventura JL, Garrido E and Segura R (1997). Creatine supplementation does not improve physical performance in a 150 m race. Rev Esp Fisiol. 53 (4): 343-8. Summary: Creatine supplementation has been shown by several authors to improve physical performance in very high intensity, intermittent, exercises. The effect on performance, as well as in plasma creatine and lactate concentrations has been studied in a group of twelve sprinters of national class when running a distance of 150 m on two occasions, before and after creatine (or placebo) supplementation for the previous three days. The most important differences in the biochemical parameters analyzed have been in plasma creatinine concentration, which increased substantially both before and after the race in the group that had received a daily supplement of 25 grams of creatine monohydrate for the previous three days. Creatine supplementation, therefore, did not improve physical performance, in the conditions, when running a 150 m distance. Depto. de Ciencias Fisiologicas y Nutricion, Facultad de Medicina, Universidad de Barcelona, Spain.

  Jeong KS, Park SJ, Lee CS, Kim TW, Kim SH, Ryu SY, Williams BH, Veech RL and Lee YS (2000). Effects of cyclocreatine in rat hepatocarcinogenesis model. Anticancer Res. 20 (3A): 1627-33. Summary: Cyclocreatine (CCr), a substrate analogue of creatine kinase (CK: EC, exhibits anti-tumor activity in vitro and in vivo. We examined the effects of CCr on the hepatocarcinogenesis of F344 rats caused by treatment with diethylnitrosamine (DEN), partial hepatectomy (PH) or 2-acetylaminofluorene (2-AAF). The rats were given a single intraperitoneal injection of 200 mg of DEN per kg in 0.85% NaCl solution at four weeks of age. Two weeks later they were divided into two groups. One group was continuously fed a commercial powder diet containing 0.02% 2-AAF for 12 weeks and the other was continuously fed a commercial powder diet containing 1% CCr plus 0.02% 2-AAF for 12 weeks. A third group of rats as a control was given only a normal powder diet for 12 weeks. All the groups were subjected to a two-thirds partial hepatectomy (PH) at 3 weeks under avertin anesthesia. To elucidate the inhibitory effect of CCr on chemical induced hepatocarcinogenesis, we examined not only the distribution of glutathione-S-transferase placental form (GST-P) a marker used for tumorigenesis, but also the inhibition of the degree of apoptosis. The number (No./cm2) and area (mm2/cm2) of GST-P positive liver foci were significantly lower in the 2-AAF + CCr treated when compared to the group treated with 2-AAF only. Our data suggest that CCr inhibits the degrees of GST-P-positive cells and apoptosis and is active against hepatocarcinogenesis in rat models. This result points out the unique nature of an anticancer agent that inhibits progression of chemically induced hepatocarcinogenesis of rats. Laboratory of Membrane Biochemistry and Biophysics, NIAAA, National Institutes of Health, Bethesda, MD 20852-8115, USA.

  Jones AM, Carter H, Pringle JS and Campbell IT (2002). Effect of creatine supplementation on oxygen uptake kinetics during submaximal cycle exercise. J Appl Physiol. 92 (6): 2571-7. Summary: The purpose of this study was to test the effect of oral creatine (Cr) supplementation on pulmonary oxygen uptake (VO(2)) kinetics during moderate [below ventilatory threshold (VT)] and heavy (above VT) submaximal cycle exercise. Nine subjects (7 men; means +/- SD: age 28 +/- 3 yr, body mass 73.2 +/- 5.6 kg, maximal VO(2) 46.4 +/- 8.0 ml. kg(-1). min(-1)) volunteered to participate in this study. Subjects performed transitions of 6-min duration from unloaded cycling to moderate (80% VT; 8-12 repeats) and heavy exercise (50% change; i.e., halfway between VT and maximal VO(2); 4-6 repeats), both in the control condition and after Cr loading, in a crossover design. The Cr loading regimen involved oral consumption of 20 g/day of Cr monohydrate for 5 days, followed by a maintenance dose of 5 g/day thereafter. VO(2) was measured breath by breath and modeled by using two (moderate) or three (heavy) exponential terms. For moderate exercise, there were no differences in the parameters of the VO(2) kinetic response between control and Cr-loaded conditions. For heavy exercise, the time-based parameters of the VO(2) response were unchanged, but the amplitude of the primary component was significantly reduced with Cr loading (means +/- SE: control 2.00 +/- 0.12 l/min; Cr loaded 1.92 +/- 0.10 l/min; P < 0.05) as was the end-exercise VO(2) (control 2.19 +/- 0.13 l/min; Cr loaded 2.12 +/- 0.14 l/min; P < 0.05). The magnitude of the reduction in submaximal VO(2) with Cr loading was significantly correlated with the percentage of type II fibers in the vastus lateralis (r = 0.87; P < 0.01; n = 7), indicating that the effect might be related to changes in motor unit recruitment patterns or the volume of muscle activated. Department of Exercise and Sport Science, Manchester Metropolitan University, Alsager ST7 2HL, United Kingdom.

  Klopstock T, Querner V, Schmidt F, Gekeler F, Walter M, Hartard M, Henning M, Gasser T, Pongratz D, Straube A, Dieterich M and Muller-Felber W (2000). A placebo-controlled crossover trial of creatine in mitochondrial diseases. Neurology. 55 (11): 1748-51. Summary: To test the efficacy and safety of creatine (Cr) monohydrate in mitochondrial diseases, 16 patients with chronic progressive external ophthalmoplegia or mitochondrial myopathy were randomized in a crossover design to receive double-blind placebo or 20 g Cr/day for 4 weeks. Cr was well tolerated, but there were no significant effects with regard to exercise performance, eye movements, or activities of daily life. The power of this pilot study was limited and future multicenter trials are needed. Department of Neurology, Ludwig-Maximilians-Universitat Munchen, Germany. klopstock@brain.nefo.med.uni-muenchen.de.

  Kreider RB, Ferreira M, Wilson M, Grindstaff P, Plisk S, Reinardy J, Cantler E and Almada AL (1998). Effects of creatine supplementation on body composition, strength, and sprint performance. Med Sci Sports Exerc. 30 (1): 73-82. Summary: PURPOSE: To determine the effects of 28 d of creatine supplementation during training on body composition, strength, sprint performance, and hematological profiles. METHODS: In a double-blind and randomized manner, 25 NCAA division IA football players were matched-paired and assigned to supplement their diet for 28 d during resistance/agility training (8 h x wk[-1]) with a Phosphagen HP (Experimental and Applied Sciences, Golden, CO) placebo (P) containing 99 g x d(-1) of glucose, 3 g x d(-1) of taurine, 1.1 g x d(-1) of disodium phosphate, and 1.2 g x d(-1) of potassium phosphate (P) or Phosphagen HP containing the P with 15.75 g x d(-1) of HPCE pure creatine monohydrate (HP). Before and after supplementation, fasting blood samples were obtained; total body weight, total body water, and body composition were determined; subjects performed a maximal repetition test on the isotonic bench press, squat, and power clean; and subjects performed a cycle ergometer sprint test (12 x 6-s sprints with 30-s rest recovery). RESULTS: Hematological parameters remained within normal clinical limits for active individuals with no side effects reported. Total body weight significantly increased (P < 0.05) in the HP group (P 0.85 +/- 2.2; HP 2.42 +/- 1.4 kg) while no differences were observed in the percentage of total body water. DEXA scanned body mass (P 0.77 +/- 1.8; HP 2.22 +/- 1.5 kg) and fat/bone-free mass (P 1.33 +/- 1.1; HP 2.43 +/- 1.4 kg) were significantly increased in the HP group. Gains in bench press lifting volume (P -5 +/- 134; HP 225 +/- 246 kg), the sum of bench press, squat, and power clean lifting volume (P 1,105 +/- 429; HP 1,558 +/- 645 kg), and total work performed during the first five 6-s sprints was significantly greater in the HP group. CONCLUSION: The addition of creatine to the glucose/taurine/electrolyte supplement promoted greater gains in fat/bone-free mass, isotonic lifting volume, and sprint performance during intense resistance/agility training. Department of Human Movement Sciences & Education, The University of Memphis, TN 38152, USA. kreider.richard@coe.memphis.edu.

  Maddock RJ, Bidner BS, Carr SN, McKeith FK, Berg EP and Savell JW (2002). Creatine monohydrate supplementation and the quality of fresh pork in normal and halothane carrier pigs. J Anim Sci. 80 (4): 997-1004. Summary: The objective of this research was to examine the impact of supplementation with creatine monohydrate (CMH) on the quality of various muscles from normal and heterozygous halothane carrier pigs. Twenty-nine crossbred pigs, 16 normal (NN) and 13 halothane carrier (Nn) genotypes, were supplemented with 0 or 25 g x pig(-1) x d(-1) of CMH for 5 d before slaughter. Supplemented pigs gained 2.26 kg more weight (P < 0.05) during 5 d of supplementation. There were trends (P < 0.10) toward higher objective marbling scores and lower cooking loss for supplemented pigs. The 45-min pH was 0.27 units higher (P < 0.05) for supplemented pigs in the semimembranosus; CMH supplementation did not influence (P > 0.05) drip loss or muscle composition. Supplementation with CMH also resulted in lower L* values in two ham muscles, semitendinosus (5.15 units) (P < 0.05) and semimembranosus (1.95 units) (P < 0.10) for Nn carcasses. Genotype had significant effects on most quality indicators, with Nn carcasses producing lower-quality lean as evidenced by less desirable subjective and objective color and higher drip losses. Genotype also affected the composition of several muscles, with the NN carcasses having more fat and less moisture. Department of Animal Sciences, Texas A & M University, College Station 77843-2471, USA. robert_maddock@sdstate.edu.

  Maril N, Degani H, Rushkin E, Sherry AD and Cohn M (1999). Kinetics of cyclocreatine and Na(+) cotransport in human breast cancer cells: mechanism of activity. Am J Physiol. 277 (4 Pt 1): C708-16. Summary: The growth-inhibitory effect of cyclocreatine (CCr) and the kinetics of CCr and Na(+) cotransport were investigated in MCF7 human breast cancer cells and its adriamycin-resistant subline with use of (31)P- and (23)Na-NMR spectroscopy. The growth-inhibitory effect in the resistant line occurred at a lower CCr concentration and was more pronounced than in the wild-type line. This correlated with an approximately 10-fold higher affinity of CCr to the transporter in the resistant line. The passive diffusion coefficient of CCr was also higher in the resistant line by three- to fourfold. The transport of CCr was accompanied by a rapid increase in intracellular Na(+). This increase was found to depend on the rate of CCr transport and varied differently with CCr concentration in the two cell lines. It is proposed that the cotransport of CCr and Na(+) followed by increased Na(+) concentration, together with the accumulation of the highly charged phosphocyclocreatine, are responsible for cell swelling and death. Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.

  Maughan R (2002). The athlete's diet: nutritional goals and dietary strategies. Proc Nutr Soc. 61 (1): 87-96. Summary: When talented, motivated and highly trained athletes meet for competition the margin between victory and defeat is usually small. When everything else is equal, nutrition can make the difference between winning and losing. Although the primary concern of many athletes is to supplement the diet with protein, vitamins and minerals, and a range of more exotic compounds, key dietary issues are often neglected. Athletes must establish their nutritional goals, and must also be able to translate them into dietary strategies that will meet these goals. Athletes are often concerned with dietary manipulations in the period around competition, but the main role of nutrition may be to support consistent intensive training which will lead to improved performance. Meeting energy demand and maintaining body mass and body fat at appropriate levels are key goals. An adequate intake of carbohydrate is crucial for maintaining muscle glycogen stores during hard training, but the types of food and the timing of intake are also important. Protein ingestion may stimulate muscle protein synthesis in the post-exercise period, promoting the process of adaptation in the muscles. Restoration of fluid and electrolyte balance after exercise is essential. If energy intake is high and a varied diet is consumed, supplementation of the diet with vitamins and minerals is not warranted, unless a specific deficiency is identified. Specific strategies before competition may be necessary, but this requirement depends on the demands of the sport. Generally, it is important to ensure high pre-competition glycogen stores and to maintain fluid balance. There is limited evidence to support the use of dietary supplements, but some, including perhaps creatine and caffeine, may be beneficial. University Medical School, Aberdeen, UK. r.maughan@abdn.ac.uk.

  McNaughton LR, Dalton B and Tarr J (1998). The effects of creatine supplementation on high-intensity exercise performance in elite performers. Eur J Appl Physiol Occup Physiol. 78 (3): 236-40. Summary: The aim of this research was to determine whether creatine supplementation at a dose of 20 g x day(-1), given in 4 x 6-g doses (5 g creatine monohydrate and 1 g glucose) for 5 days, was effective in improving kayak ergometer performances of different durations. Sixteen male subjects with the following characteristics [mean (SEM)]: age 21 (1.2) years, height 170.2 (1.7) cm, weight 75.3 (2.3) kg, sigma8 skinfolds 59.3 (2.6) mm, and maximal oxygen consumption 67.1 +/- (4.3) ml x kg x min(-1), undertook three maximal kayak ergometer tests of 90, 150 and 300 s duration on a wind-braked kayak ergometer (CON). Two groups were then randomly formed, with one group taking the supplement (SUP) while the other took a placebo (PLAC). No pre-test differences existed between the SUP and the PLAC groups in any of the variables measured. After supplementation each group then repeated the same kayak ergometer tests as performed previously and after a 4-week "washout period" the groups took either the PLAC or SUP for another 5 days and then completed the final tests. The SUP group completed significantly more work than either the CON or PLAC groups in all of the tests (90 s, P < 0.01; 150 s, P < 0.001; 300 s, P < 0.05). Body mass remained stable throughout the test period in both the CON and PLAC groups, but both were significantly less than the SUP body mass of 77.3 (1.0) kg (P < 0.01). The results of this work indicate that creatine supplementation can significantly increase the amount of work accomplished during kayak ergometer performance at durations ranging from 90 to 300 s. Kingston University, Kingston upon Thames, Survey, UK.

  Michaelis T, Wick M, Fujimori H, Matsumura A and Frahm J (1999). Proton MRS of oral creatine supplementation in rats. Cerebral metabolite concentrations and ischemic challenge. NMR Biomed. 12 (5): 309-14. Summary: Proton magnetic resonance spectroscopy (MRS) was employed to determine the concentrations of N-acetylaspartate (NAA), total creatine (tCr), choline-containing compounds (Cho), myo-inositol (Ins), glucose (Glc), and lactate (Lac) in rat brain before and after 10 days of oral supplementation of 2.6 g Cr-monohydrate per kg body weight per day. Measurements were performed both in vitro (n = 16) and in vivo (n = 6). The neuroprotective potential of oral Cr was assessed by dynamically monitoring brain Glc and Lac in response to transient global ischemia (12 min). In comparison to controls the in vitro concentrations of Cr (13.1 +/- 9.3%) and Ins (12.7 +/- 14. 0%) were significantly increased in Cr-fed rats. Under in vivo conditions, the data revealed trends for elevated tCr (4.7%) and Ins (10.6%) which were enhanced in the concentration ratios of tCr:Cho (10.2%) and Ins:Cho (17.8%). Together with an increased Glc level (27.3%), the observation of a statistically significant decrease of brain Lac (-38.5 +/- 19.3%) in Cr-fed rats may reflect a shift of the energy metabolism from non-oxidative toward oxidative glycolysis. One hour after global ischemia most of the metabolic differences between Cr-fed rats and controls were retained. The increased Glc level (44.4 +/- 33.3%) reached statistical significance, but the accumulation of Lac and its time course during ischemia and early reperfusion showed no differences between Cr-fed rats and controls. Biomedizinische NMR Forschungs GmbH am Max-Planck-Institut fur biophysikalische Chemie, D-37070 Gottingen, Germany. tmichae@gwdg.de.

  Mihic S, MacDonald JR, McKenzie S and Tarnopolsky MA (2000). Acute creatine loading increases fat-free mass, but does not affect blood pressure, plasma creatinine, or CK activity in men and women. Med Sci Sports Exerc. 32 (2): 291-6. Summary: Creatine monohydrate (CrM) administration may enhance high intensity exercise performance and increase body mass, yet few studies have examined for potential adverse effects, and no studies have directly considered potential gender differences. PURPOSE: The purpose of this study was to examine the effect of acute creatine supplementation upon total and lean mass and to determine potential side effects in both men and women. METHODS: The effect of acute CrM (20 g x d(-1) x 5 d) administration upon systolic, diastolic, and mean BP, plasma creatinine, plasma CK activity, and body composition was examined in 15 men and 15 women in a randomized, double-blind experiment. Additionally, ischemic isometric handgrip strength was measured before and after CrM or placebo (PL). RESULTS: CrM did not affect blood pressure, plasma creatinine, estimated creatinine clearance, plasma CK activity, or handgrip strength (P > 0.05). In contrast, CrM significantly increased fat-free mass (FFM) and total body mass (P < 0.05) as compared with PL, with no changes in body fat. The observed mass changes were greater for men versus women. CONCLUSIONS: These findings suggest that acute CrM administration does not affect blood pressure, renal function, or plasma CK activity, but increases FFM. The effect of CrM upon FFM may be greater in men as compared with that in women. Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada.

  Miura A, Kino F, Kajitani S, Sato H and Fukuba Y (1999). The effect of oral creatine supplementation on the curvature constant parameter of the power-duration curve for cycle ergometry in humans. Jpn J Physiol. 49 (2): 169-74. Summary: For high-intensity cycle ergometer exercise, the tolerable duration (t) is well characterized as a hyperbolic function of power output, P : t = W'/(P-thetaF), where thetaF may be termed the "fatigue threshold." The purpose of this study was to determine the effect of oral creatine (Cr) supplementation on the curvature constant parameter (W') of the power-duration curve. A double-blind research method and a cross-over design were employed for creatine/placebo supplementation. Eight healthy male subjects (aged 18 to 22 years) each performed four or five high-intensity square-wave exercise bouts on an electrically braked cycle ergometer after 5 d of Cr monohydrate (CR: 20 g of Cr with artificial sweetener/d) or placebo (PL: 6 g of glucose/d) supplementation. Each subject performed a single high-intensity exercise trial per day for four or five successive days to determination the P-t hyperbolic relation. After 6 weeks (the washout time of Cr from the muscles), each subject performed the other condition (i.e., PL or CR) and repeated the same experimental procedure. There was no significant difference for thetaF between PL and CR conditions (PL: 214.4 +/- 23.6, CR: 207.0 +/- 19.8 W, mean +/- SD). In contrast, W' was significantly increased by the Cr supplementation (PL: 10.9 +/- 2.7, CR: 13.7 +/- 3.0 kJ; p<0.05). The results indicated that Cr and/or PCr content in muscles seems to be one of the important determinants of the curvature constant parameter (W') of the power-duration hyperbolic curve for cycle ergometry. Department of Exercise Science and Physiology, School of Health Sciences, Hiroshima Women's University, Hiroshima, 734-8558, Japan. miura@hirojo-u.ac.jp.

  Mujika I, Chatard JC, Lacoste L, Barale F and Geyssant A (1996). Creatine supplementation does not improve sprint performance in competitive swimmers. Med Sci Sports Exerc. 28 (11): 1435-41. Summary: This study was conducted to examine the effects of creatine (Cr) supplementation on sprint swimming performance and energy metabolism. Twenty highly trained swimmers (9 female, 11 male) were tested for blood ammonia and for blood lactate after the 25-, 50-, and 100-m performance in their best stroke on two occasions 7 d apart. After the first trial, subjects were evenly and randomly assigned to either a creatine (5 g creatine monohydrate 4 times per day for 5 d) or a placebo group (same dosage of a lactose placebo) in a double-blind research design. No significant differences in performance times were observed between trials. Post-exercise blood ammonia concentration decreased in the 50- and 100-m trials in the creatine group and in the 50-m trial in the placebo group. The supplementation period had no effect on post-exercise blood lactate. Therefore, creatine supplementation cannot be considered as an ergogenic aid for sprint performance in highly trained swimmers although adenine nucleotide degradation may be reduced during sprint exercise after 5 d of creatine ingestion. Laboratoire de Physiologie-GIP Exercice, Faculte de Medecine, Universite Jean Monnet, Saint-Etienne, France.

  Nelson AG, Day R, Glickman-Weiss EL, Hegsted M, Kokkonen J and Sampson B (2000). Creatine supplementation alters the response to a graded cycle ergometer test. Eur J Appl Physiol. 83 (1): 89-94. Summary: To determine the effects of creatine supplementation on cardiorespiratory responses during a graded exercise test (GXT) 36 trained adults (20 male, 16 female; 21-27 years old) performed two maximal GXTs on a cycle ergometer. The first GXT was done in a nonsupplemented condition, and the second GXT was done following 7 days of ingesting either 5 g creatine monohydrate, encased in gelatin capsules, four times daily (CS, 13 male, 6 female), or the same number of glucose capsules (PL, 7 male, 10 female). CS significantly (P<0.05) improved total test time [pre-CS = 1217 (240) s, mean (std. dev.) versus post-CS = 1289 (215) s], while PL administration had no effect (P>0.05) on total test time [pre-PL= 1037 (181) s. versus post-PL= 1047 (172) s]. In addition, both oxygen consumption (VO2) and heart rate at the end of each of the first five GXT stages were significantly lower after CS, but were unchanged after PL. Moreover, the ventilatory threshold occurred at a significantly greater VO2 for CS [pre-CS = 2.2 (0.4) l x min(-1) or 66% of peak VO2 versus post-CS = 2.6 (0.5) l x min(-1) or 78% of peak Vo2; pre-PL = 2.6 (0.9) l x min(-1) or 70% peak VO2 versus post-PL = 2.6 (1.1) l x min(-1) or 68% of peak Vo2]. Neither CS nor PL had an effect on peak Vo2 [pre-CS = 3.4 (0.7) l x min(-1) versus post-CS = 3.3 (0.7) l x min(-1); pre-PL = 3.7 (1.1) l x min(-1) versus post-PL = 3.7 (1.1) l x min(-1)]. Apparently, CS can alter the contributions of the different metabolic systems during the initial stages of a GXT. Thus, the body is able to perform the sub-maximal workloads at a lower oxygen cost with a concomitant reduction in the work performed by the cardiovascular system. Department of Kinesiology, Louisiana State University, Baton Rouge 70803, USA. anelso@lsu.edu.

  Odland LM, MacDougall JD, Tarnopolsky MA, Elorriaga A and Borgmann A (1997). Effect of oral creatine supplementation on muscle [PCr] and short-term maximum power output. Med Sci Sports Exerc. 29 (2): 216-9. Summary: Our purpose was to determine the effect of creatine supplementation on power output during a 30-s maximal cycling (Wingate) test. Nine males underwent 3 randomly ordered tests following ingestion of a creatine supplementation (CRE), placebo (PLA), and control (CON) CRE was ingested as creatine monohydrate (CrH2O) dissolved in a flavored drink (20g.d-1 for 3 d), while PLA consisted of the drink only. Tests were performed 14 d apart on a Monarch ergometer modified for immediate resistance loading. Needle biopsies were taken from the vastus lateralis at the end of each treatment period and before the exercise test. No difference was found between conditions for peak, mean 10-s, and mean 30-s power output, percent fatigue, or post-exercise blood lactate concentration. Similarly, no difference between conditions was observed for ATP, phosphocreatine (PCr), or total creatine (TCr); however, the TCr/ATP was higher in the CRE condition (P < 0.05) than in the CON and PLA conditions. Findings suggest that 3 d of oral Cr supplementation does not increase resting muscle PCr concentration and has no effect on performance during a single short-term maximal cycling task. Department of Kinesiology, McMaster University, Hamilton, ON, Canada.

  Op 't Eijnde B and Hespel P (2001). Short-term creatine supplementation does not alter the hormonal response to resistance training. Med Sci Sports Exerc. 33 (3): 449-53. Summary: PURPOSE: In this study, the effect of short-term creatine supplementation on the growth hormone, testosterone, and cortisol response to heavy resistance training was investigated. METHODS: According to a double-blind crossover study design, 11 healthy young male volunteers underwent a 1-h standardized heavy resistance training session (3 series of 10RM; 12 exercises), both before (pretest) and after (posttest) 5 d of either placebo (P, maltodextrine) or creatine (CR; 20 g.d-1, 5 d) supplementation. A 5-wk washout period separated the treatments. Thirty minutes before each training session, CR subjects ingested 10 g of creatine monohydrate (CR) while P subjects received placebo. Venous blood was sampled before, immediately after, and 30 and 60 min after the training session. RESULTS: The exercise-induced increase (P < 0.05) of serum growth hormone was not altered by acute creatine intake and was similar in P and CR. The weight training session, either or not in conjunction with acute or chronic creatine intake, did not significantly impact on serum testosterone. However, serum cortisol during recovery tended to be higher in CR than in P. CONCLUSION: It is concluded that short-term creatine supplementation does not alter the responses of growth hormone, testosterone, and cortisol to a single bout of heavy resistance training. Faculty of Physical Education and Physiotherapy, Department of Kinesiology, Exercise Physiology and Biomechanics Laboratory, Katholieke Universiteit Leuven, Belgium.

  O'Quinn PR, Andrews BS, Goodband RD, Unruh JA, Nelssen JL, Woodworth JC, Tokach MD and Owen KQ (2000). Effects of modified tall oil and creatine monohydrate on growth performance, carcass characteristics, and meat quality of growing-finishing pigs. J Anim Sci. 78 (9): 2376-82. Summary: The effects of feeding modified tall oil (MTO) and creatine monohydrate (CMH) on growing-finishing pig growth performance, carcass characteristics, and meat quality were determined. Eighty cross-bred barrows (initially 45.4 kg) were allotted randomly to one of four dietary treatments by weight and ancestry. The experiment was arranged as a 2 x 2 factorial with two levels of MTO (0 or 0.50%), which were fed throughout the growing-finishing period, and two levels of CMH (0 or 25 g/d), which were fed for the final 10 d before slaughter. The corn-soybean meal diets were fed in two phases (45.4 to 78.9 kg and 78.9 to 117.5 kg BW). When CMH was added to the diet in place of corn, average BW was 107.5 kg. Feeding MTO increased (P < 0.05) ADG and gain:feed ratio (G/F) during the 45.4- to 78.9-kg growth interval and tended to improve (P = 0.10) G/F during the 45.4- to 107.5-kg growth interval. Dietary treatment did not affect (P > 0.15) growth performance during the 78.9- to 107.5-kg growth interval. Modified tall oil increased (P = 0.02) G/F during the 10-d CMH supplementation period, and CMH numerically (P = 0.11) increased ADG and G/F. Supplementation of CMH did not affect (P > 0.20) any measured carcass characteristic or measures of meat quality at 24 h or 14 d postmortem. Feeding MTO reduced average back-fat (P = 0.05) and 10th rib backfat (P = 0.01) but did not affect (P > 0.10) other measured carcass characteristics or measures of meat quality at 24 h postmortem. Modified tall oil increased (P = 0.02) L* values (lightness) and tended to increase (P < 0.10) thawing and cooking losses of longissimus muscle chops at 14 d postmortem. These data demonstrate that MTO improves growth performance and reduces backfat in growing-finishing pigs, but supplementation of CMH, under the conditions of this experiment, was not beneficial for growing-finishing pigs. Department of Animal Sciences and Industry, Kansas State University, Manhattan 66506, USA.

  Parise G, Mihic S, MacLennan D, Yarasheski KE and Tarnopolsky MA (2001). Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis. J Appl Physiol. 91 (3): 1041-7. Summary: Creatine monohydrate (CrM) supplementation during resistance exercise training results in a greater increase in strength and fat-free mass than placebo. Whether this is solely due to an increase in intracellular water or whether there may be alterations in protein turnover is not clear at this point. We examined the effects of CrM supplementation on indexes of protein metabolism in young healthy men (n = 13) and women (n = 14). Subjects were randomly allocated to CrM (20 g/day for 5 days followed by 5 g/day for 3-4 days) or placebo (glucose polymers) and tested before and after the supplementation period under rigorous dietary and exercise controls. Muscle phosphocreatine, creatine, and total creatine were measured before and after supplementation. A primed-continuous intravenous infusion of L-[1-(13)C]leucine and mass spectrometry were used to measure mixed-muscle protein fractional synthetic rate and indexes of whole body leucine metabolism (nonoxidative leucine disposal), leucine oxidation, and plasma leucine rate of appearance. CrM supplementation increased muscle total creatine (+13.1%, P < 0.05) with a trend toward an increase in phosphocreatine (+8.8%, P = 0.09). CrM supplementation did not increase muscle fractional synthetic rate but reduced leucine oxidation (-19.6%) and plasma leucine rate of appearance (-7.5%, P < 0.05) in men, but not in women. CrM did not increase total body mass or fat-free mass. We conclude that short-term CrM supplementation may have anticatabolic actions in some proteins (in men), but CrM does not increase whole body or mixed-muscle protein synthesis. Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.

  Persky AM and Brazeau GA (2001). Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev. 53 (2): 161-76. Summary: Creatine is a dietary supplement purported to improve exercise performance and increase fat-free mass. Recent research on creatine has demonstrated positive therapeutic results in various clinical applications. The purpose of this review is to focus on the clinical pharmacology and therapeutic application of creatine supplementation. Creatine is a naturally occurring compound obtained in humans from endogenous production and consumption through the diet. When supplemented with exogenous creatine, intramuscular and cerebral stores of creatine and its phosphorylated form, phosphocreatine, become elevated. The increase of these stores can offer therapeutic benefits by preventing ATP depletion, stimulating protein synthesis or reducing protein degradation, and stabilizing biological membranes. Evidence from the exercise literature has shown athletes benefit from supplementation by increasing muscular force and power, reducing fatigue in repeated bout activities, and increasing muscle mass. These benefits have been applied to disease models of Huntington's, Parkinson's, Duchenne muscular dystrophy, and applied clinically in patients with gyrate atrophy, various neuromuscular disorders, McArdle's disease, and congestive heart failure. This review covers the basics of creatine synthesis and transport, proposed mechanisms of action, pharmacokinetics of exogenous creatine administration, creatine use in disease models, side effects associated with use, and issues on product quality. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA. apersky@ufl.edu.

  Poortmans JR, Auquier H, Renaut V, Durussel A, Saugy M and Brisson GR (1997). Effect of short-term creatine supplementation on renal responses in men. Eur J Appl Physiol Occup Physiol. 76 (6): 566-7. Summary: There is an increasing utilisation of oral creatine (Cr) supplementation among athletes who hope to enhance their performance but it is not known if this ingestion has any detrimental effect on the kidney. Five healthy men ingested either a placebo or 20 g of creatine monohydrate per day for 5 consecutive days. Blood samples and urine collections were analysed for Cr and creatinine (Crn) determination after each experimental session. Total protein and albumin urine excretion rates were also determined. Oral Cr supplementation had a significant incremental impact on arterial content (3.7 fold) and urine excretion rate (90 fold) of this compound. In contrast, arterial and urine Crn values were not affected by the Cr ingestion. The glomerular filtration rate (Crn clearance) and the total protein and albumin excretion rates remained within the normal range. In conclusion, this investigation showed that short-term oral Cr supplementation does not appear to have any detrimental effect on the renal responses of healthy men. Chimie Physiologique, Institut Superieur d'Education Physique et de Kinesitherapie, Universite Libre de Bruxelles, Belgium.

  Poortmans JR and Francaux M (2000). Adverse effects of creatine supplementation: fact or fiction? Sports Med. 30 (3): 155-70. Summary: The consumption of oral creatine monohydrate has become increasingly common among professional and amateur athletes. Despite numerous publications on the ergogenic effects of this naturally occurring substance, there is little information on the possible adverse effects of this supplement. The objectives of this review are to identify the scientific facts and contrast them with reports in the news media, which have repeatedly emphasised the health risks of creatine supplementation and do not hesitate to draw broad conclusions from individual case reports. Exogenous creatine supplements are often consumed by athletes in amounts of up to 20 g/day for a few days, followed by 1 to 10 g/day for weeks, months and even years. Usually, consumers do not report any adverse effects, but body mass increases. There are few reports that creatine supplementation has protective effects in heart, muscle and neurological diseases. Gastrointestinal disturbances and muscle cramps have been reported occasionally in healthy individuals, but the effects are anecdotal. Liver and kidney dysfunction have also been suggested on the basis of small changes in markers of organ function and of occasional case reports, but well controlled studies on the adverse effects of exogenous creatine supplementation are almost nonexistent. We have investigated liver changes during medium term (4 weeks) creatine supplementation in young athletes. None showed any evidence of dysfunction on the basis of serum enzymes and urea production. Short term (5 days), medium term (9 weeks) and long term (up to 5 years) oral creatine supplementation has been studied in small cohorts of athletes whose kidney function was monitored by clearance methods and urine protein excretion rate. We did not find any adverse effects on renal function. The present review is not intended to reach conclusions on the effect of creatine supplementation on sport performance, but we believe that there is no evidence for deleterious effects in healthy individuals. Nevertheless, idiosyncratic effects may occur when large amounts of an exogenous substance containing an amino group are consumed, with the consequent increased load on the liver and kidneys. Regular monitoring is compulsory to avoid any abnormal reactions during oral creatine supplementation. Physiological Chemistry, Higher Institute of Physical Education and Readaptation, Free University of Brussels, Bruxelles, Belgium. jrpoortm@ulb.ac.be.

  Prevost MC, Nelson AG and Morris GS (1997). Creatine supplementation enhances intermittent work performance. Res Q Exerc Sport. 68 (3): 233-40. Summary: To determine the impact of creatine supplementation on high-intensity, intermittent work, 18 participants each performed 2 sets of 4 different work bouts to exhaustion. For 5 days prior to the first set of work bouts, all participants received a placebo (5 g of calcium chloride daily). For the second set of work bouts, 9 participants again received the placebo, while the other 9 received creatine supplementation (18.75 g creatine monohydrate daily for 5 days prior to and 2.25 g creatine daily during testing). The four work bouts in each set consisted of cycling to exhaustion at 150% peak oxygen uptake (VO2peak) either nonstop (A), intermittently for either 60-s work/120-s rest periods (B), 20-s work/40-s rest (C), or 10-s work/20-s rest (D). Creatine supplementation significantly increased (p < .01) the total work time of all bouts. Protocol D showed the greatest increase (> 100%); C increased 61.9%; B increased 61.0%; and A increased 23.5%. These results demonstrate that creatine supplementation significantly extends one's capacity to maintain a specific level of high-intensity, intermittent exercise. Marine Corps Air Station, EI Toro, USA.

  Puri BK, Smith HC, Cox IJ, Sargentoni J, Savic G, Maskill DW, Frankel HL, Ellaway PH and Davey NJ (1998). The human motor cortex after incomplete spinal cord injury: an investigation using proton magnetic resonance spectroscopy. J Neurol Neurosurg Psychiatry. 65 (5): 748-54. Summary: OBJECTIVES:(1) A biochemical investigation of the motor cortex in patients with incomplete spinal cord injury and normal control subjects using proton magnetic resonance spectroscopy (MRS). (2) To relate any altered biochemistry with the physiological changes in corticospinal function seen after spinal cord injury. METHODS: A group of six patients with incomplete spinal cord injury who showed good recovery of motor function were selected. The patients were compared with five healthy control subjects. Electromyographic (EMG) responses of thenar muscles to transcranial magnetic stimulation (TMS) of the motor cortex showed that inhibition of cortical output was weaker in the patients than the controls. Proton MRS data were collected from a plane at the level of the centrum semiovale. Two 4.5 cm3 voxels in the motor cortex and a third voxel in the ipsilateral occipital cortex were examined in the patients and control subjects. RESULTS: The mean level of N-acetylaspartate (NAA), expressed relative to the creatine (Cr) peak (NAA/Cr), was significantly increased in the motor cortex of the patients compared with their ipsilateral occipital cortex or either cortical area in the controls. No differences between patients and controls were seen for any of the other metabolite peaks (choline (Cho), glutamate/glutamine (Glx) or the aspartate component of NAA (AspNAA)) relative to Cr. Choline relative to Cr (Cho/Cr) was higher in the motor cortex of the control subjects than in their ipsilateral occipital cortex. This difference was not present in the patients. CONCLUSIONS: Raised NAA/Cr in the motor cortex of the patients probably results from increased NAA rather than a decrease in the more stable Cr. The possible relevance of a raised NAA/Cr ratio is discussed, particularly with regard to the changed corticospinal physiology and the functional recovery seen in the patients. Robert Steiner MRI Unit, Imperial College School of Medicine, Hammersmith Hospital, London, UK.

  Redondo DR, Dowling EA, Graham BL, Almada AL and Williams MH (1996). The effect of oral creatine monohydrate supplementation on running velocity. Int J Sport Nutr. 6 (3): 213-21. Summary: Creatine supplementation has been shown to augment muscle PCr content and increase the rate of ATP resynthesis. Thus, we hypothesized that creatine supplementation might enhance sprinting performance. Eighteen subjects completed both of two testing sessions (control and postsupplement) 1 week apart, wherein they sprinted three 60-m distance trials that were recorded with videotape. Following the control session, for 7 days, subjects in the treatment group ingested a creatine-glucose mixture, while the placebo group consumed a glucose powder, followed by the postsupplementation session. Velocities of the subjects through three testing zones within the 60-m sprint were calculated from the videotape. Resultant velocities were analyzed using a MANOVA with a 2 x 2 x 3 x 3 (Group x Session x Trial x Zone) design. Results indicated that there were no statistically significant main or interaction effects on velocity between groups for session, trial, or zone. These data do not support the hypothesis that supplementary creatine ingestion will enhance velocity during the early or latter segments of a 60-m sprint. Department of Exercise Science, Physical Education, and Recreation, Old Dominion University, Norfolk, VA 23529-0196, USA.

  Rico-Sanz J and Mendez Marco MT (2000). Creatine enhances oxygen uptake and performance during alternating intensity exercise. Med Sci Sports Exerc. 32 (2): 379-85. Summary: PURPOSE: The main purpose of the present study was to measure the total oxygen consumed, accumulation of blood metabolites, and performance during alternating intensity exercise before and after a period of creatine (Cr) loading in well-trained humans. METHODS: Fourteen males were randomly assigned to two groups of seven males and were tested before and after 5 d of placebo (PL) or Cr monohydrate (CR) loading (20 g x d(-1)). Oxygen uptake was measured using a breath-by-breath system during bicycle exercise alternating every 3 min between bouts at 30%(-30%) and 90% (-90%) of the maximal power output to exhaustion. Blood samples were also obtained at rest, before the end of each cycling load, at exhaustion, and 5-min postexercise. RESULTS: The oxygen consumed during 1-90% (5.08 +/- 0.39 L) and 2-90% (5.32 +/- 0.30 L) was larger after CR (5.67 +/- 0.34 and 5.78 +/- 0.35 L, P < 0.01 and P < 0.05, respectively). Blood ammonia accumulation at the end of 1-90% (23.1 +/- 6.5 micromol x L(-1)) and 3-30% (64.7 +/- 15.2 micromol x L(-1)) was lower after CR (P < 0.05), whereas plasma uric acid accumulation was lower at exhaustion (P < 0.05) and 5-min postexercise (P < 0.01). Time to exhaustion increased (P < 0.05) from 29.9 +/- 3.8 to 36.5 +/- 5.7 min after CR, whereas it remained the same after PL. CONCLUSIONS: The results indicate that Cr feeding increases the capacity of human muscle to perform work during alternating intensity contraction, possibly as a consequence of increased aerobic phosphorylation and flux through the creatine kinase system. Department of Biochemistry and Molecular Biology, Faculty of Sciences, University Autonoma of Barcelona, Spain. j.rico-sanz@proton.uab.es.

  Romer LM, Barrington JP and Jeukendrup AE (2001). Effects of oral creatine supplementation on high intensity, intermittent exercise performance in competitive squash players. Int J Sports Med. 22 (8): 546-52. Summary: The purpose of this study was to determine the effects of oral creatine supplementation on high intensity, intermittent exercise performance in competitive squash players. Nine squash players (mean +/- SEM VO2max = 61.9 +/- 2.1 ml x kg(-1) x min(-1); body mass = 73 +/- 3 kg) performed an on-court "ghosting" routine that involved 10 sets of 2 repetitions of simulated positional play, each set interspersed with 30 s passive recovery. A double blind, crossover design was utilised whereby experimental and control groups supplemented 4 times daily for 5 d with 0.075 g x kg(-1) body mass of creatine monohydrate and maltodextrine, respectively, and a 4 wk washout period separated the crossover of treatments. The experimental group improved mean set sprint time by 3.2 +/- 0.8% over and above the changes noted for the control group (P = 0.004 and 95% Cl = 1.4 to 5.1%). Sets 2 to 10 were completed in a significantly shorter time following creatine supplementation compared to the placebo condition (P < 0.05). In conclusion, these data support existing evidence that creatine supplementation improves high intensity, intermittent exercise performance. In addition, the present study provides new evidence that oral creatine supplementation improves exercise performance in competitive squash players. Sports Medicine and Human Performance Unit, School of Sport and Exercise Sciences, The University of Birmingham, Edgbaston, Birmingham, UK.

  Rossiter HB, Cannell ER and Jakeman PM (1996). The effect of oral creatine supplementation on the 1000-m performance of competitive rowers. J Sports Sci. 14 (2): 175-9. Summary: This study investigated the change in 1000-m simulated rowing performance in two matched groups of 19 competitive rowers following a 5-day period of supplementation with placebo (CON group) or creatine at a dose equivalent to 0.25 g creatine monohydrate per kilogram of body mass (BM) (EXP group). Creatine uptake was calculated from the difference between the amount fed and the amount recovered in urine during each 24-h period of supplementation. Total creatine uptake for the EXP group over the 5-day period of supplementation averaged 34.9 +/- 10.9 g (range 20.1-54.9 g), which equated to 3.54 +/- 0.93 mmol kg BM-1. The estimated creatine uptake into muscle was 38.1 +/- 10.0 (range 22.6-56.6) mmol kg dry weight-1 for these subjects. After supplementation with placebo, the CON group showed no change in 1000-m rowing performance (214.0 +/- 30.9 vs 214.1 +/- 31.5 s; P = 0.88). Of these subjects, 7 decreased and 10 increased their performance times (range - 3.1 to 2.7%). By contrast, 16 of the 19 subjects in the EXP group improved their performance times. The mean improvement in rowing performance for the EXP group was 2.3 s (211.0 +/- 21.5 vs 208.7 +/- 21.8 s; P < 0.001), an overall improvement of just over 1% (range - 0.4 to 3.4%). We conclude that in competitive rowers, a 5-day period of creatine supplementation was effective in raising whole-body creatine stores, the magnitude of which provided a positive, though statistically non-significant (r = 0.426, P = 0.088), relationship with 1000-m rowing performance. School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, UK.

  Saab G, Marsh GD, Casselman Section Sign MA and Thompson RT (2002). Changes in human muscle transverse relaxation following short-term creatine supplementation. Exp Physiol. 87 (3): 383-9. Summary: The rapid increase in body mass that often occurs following creatine (Cr) supplementation is believed to be due to intracellular water retention. The purpose of this study was to determine whether Cr consumption alters the magnetic resonance (MR) transverse relaxation (T(2)) distribution of skeletal muscle. Transverse relaxation can be used to model water compartments within a cell or tissue. In this double-blind study, subjects were asked to supplement their normal diet with creatine monohydrate (20 g day(-1) for 5 days) mixed with a grape drink (Creatine group, n = 7), or the grape drink alone (Placebo group, n = 8). Phosphorous MR spectroscopy was used to determine the effectiveness of the supplementation protocol. Subjects that responded to the Cr supplementation (i.e. showed a > 5 % increase in the ratio of the levels of phosphocreatine (PCr) and ATP) were placed in the Creatine group. Both proton MR imaging and spectroscopy were used to acquire T(2) data, at 1.89 T, from the flexor digitorum profundus muscle of each subject before and after supplementation. Following the supplementation period, the Creatine group showed a gain in body mass (1.2 +/- 0.8 kg, P < 0.05, mean +/- S.D.), and an increase in PCr/ATP ratio (23.8 +/- 16.4 %, P < 0.001). Neither group showed any changes in intracellular pH or T(2) calculated from MR images. However, the spectroscopy data revealed at least three components (> 5 ms) at approximately 20, 40 and 125 ms in both groups. Only in the Creatine group was there an increase in the apparent proton concentration of the two shorter components combined (+5.0 +/- 4.7 %, P < 0.05). According to the cellular water compartment model, the changes observed in the shorter T(2) components are consistent with an increase in intracellular water. Experimental Physiology (2002) 87.3, 383-389. Department of Medical Biophysics, The University of Western Ontario, London, Ontario and The Lawson Health Research Institute and Department of Nuclear Medicine and Magnetic Resonance, St Joseph's Health Center, London, Ontario, Canada.

  Schilling BK, Stone MH, Utter A, Kearney JT, Johnson M, Coglianese R, Smith L, O'Bryant HS, Fry AC, Starks M, Keith R and Stone ME (2001). Creatine supplementation and health variables: a retrospective study. Med Sci Sports Exerc. 33 (2): 183-8. Summary: PURPOSE: Long-term safety of creatine supplementation has been questioned. This retrospective study was performed to examine markers related to health, the incidence of reported side effects and the perceived training benefits in athletes supplementing with creatine monohydrate. METHODS: Twenty-six athletes (18 M and 8 F, 24.7 +/- 9.2 y; 82.4 +/- 20.0 kg; 176.5 +/- 8.8 cm) from various sports were used as subjects. Blood was collected between 7:00 and 8:30 a.m. after a 12-h fast. Standard clinical examination was performed for CBC and 27 blood chemistries. Testosterone, cortisol, and growth hormone were analyzed using an ELISA. Subjects answered a questionnaire on dietary habits, creatine supplementation, medical history, training history, and perceived effects of supplementation. Body mass was measured using a medical scale, body composition was estimated using skinfolds, and resting heart rate and blood pressure were recorded. Subjects were grouped by supplementation length or no use: Gp1 (control) = no use (N = 7; 3 F, 4 M); Gp2 = 0.8-1.0 yr (N = 9; 2 F, 7 M); and Gp3 = 1(+) (N = 10; 3 F, 7 M). RESULTS: Creatine supplementation ranged from 0.8--4 yr. Mean loading dose for Gp2 and Gp3 was 13.7 +/- 10.0 and the maintenance dose was 9.7 +/- 5.7 g.d(-)1. Group differences were analyzed using one-way ANOVA. CONCLUSIONS: Expected gender differences were observed. Of the comparisons made among supplementation groups, only two differences for creatinine and total protein (P < 0.05) were noted. All group means fell within normal clinical ranges. There were no differences in the reported incidence of muscle injury, cramps, or other side effects. These data suggest that long-term creatine supplementation does not result in adverse health effects. Exercise Science, Appalachian State University, Boone, NC, USA.

  Schuback K, Essen-Gustavsson B and Persson SG (2000). Effect of creatine supplementation on muscle metabolic response to a maximal treadmill exercise test in Standardbred horses. Equine Vet J. 32 (6): 533-40. Summary: The aim of the present study was to investigate the effect of creatine (Cr) supplementation on muscle metabolic response in connection with a maximal treadmill exercise test, known to cause a marked anaerobic metabolic response and adenine nucleotide degradation. First, 6 Standardbred trotters performed a standardised maximal exercise test until fatigue (baseline test). The test used was an inclined incremental treadmill test in which the speed was increased by 1 m/s, starting at 7 m/s, every 60 s until the horse could no longer keep pace with the treadmill. After this baseline test, the horses were separated into 2 equal groups. One half received a dose of 25 g creatine monohydrate twice daily, and the other group were given the same dose of lactose (placebo). The supplementation period was 6.5 days, after which the maximal treadmill exercise test was performed again. A washout period of 14 days was allowed before treatments were switched between groups and a new supplementation period started. After this second supplementation period a new maximal exercise test was performed. After supplementation with creatine or placebo, horses were stopped after performing the same number of speed steps and duration of exercise as they had in the baseline test. Blood samples for analysis of plasma lactate, creatine (Cr), creatinine, hypoxanthine, xanthine and uric acid concentrations were collected at rest, during each speed step and during recovery. The total blood volume (TBV) was also determined. Muscle biopsies for analysis of muscle metabolites (adenosine triphosphate [ATP], adenosine diphosphate [ADP], adenosine monophosphate [AMP], inosine monophosphate [IMP], creatine phosphate [CP], lactate [La] and glycogen) were taken at rest, immediately post exercise and after 15 min recovery. The results showed no significant increase in plasma Cr or muscle total creatine concentration (TCr) after supplementation with Cr. At the end of exercise ATP and CP concentrations had decreased and IMP and lactate concentrations increased in muscle in all groups. Plasma lactate concentration increased during exercise and recovery and plasma uric acid concentration increased during recovery in all groups. No influence could be found in TBV after supplementation with creatine. These results show that creatine supplementation in the dosage used in this study had no influence on muscle metabolic response or TBV. Department of Large Animal Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala.

  Silber ML (1999). Scientific facts behind creatine monohydrate as sport nutrition supplement. J Sports Med Phys Fitness. 39 (3): 179-88. Summary: Currently, strong efforts are being made toward demonstrating possible risks of using pure creatine monohydrate (Cr.H2O). In this article, scientific facts and considerations are presented, which support such concern. A further attempt is made to pursue the concept of possible risks of uncontrolled supplementation in athletes with pure Cr.H2O. The problem is viewed from the scientific evidence that a highly conservative mechanism of homeostatic feed-back inhibitory self-regulation of Cr biosynthesis in the body has been evolutionary developed. It is shown that numerous features characteristic to Cr biosynthesis, metabolism, and regulation allow to interpret its stimulatory action in the body as endocrine hormone-like. Based on this assumption, a practical approach for detecting altered links in Cr metabolism and biosynthesis under conditions of pure Cr.H2O overdosing, is suggested. Strategic considerations regarding early diagnosis, prognosis, and correction of the down-regulated endogenous Cr biosynthesis in athletes on continuous pure Cr.H2O supplementation, are discussed. As a high efficient and safe alternative to pure Cr.H2O, a complex nutrition supplement formula for elite athletes is proposed, which exploits natural alpha-ketoglutarate as a vehicle for delivering exogenous low molecular biologically-active compounds, including Cr. Department of Natural Resource Sciences, Washington State University, Pullman 99164-6410, USA.

  Smith JC, Stephens DP, Hall EL, Jackson AW and Earnest CP (1998). Effect of oral creatine ingestion on parameters of the work rate-time relationship and time to exhaustion in high-intensity cycling. Eur J Appl Physiol Occup Physiol. 77 (4): 360-5. Summary: The relationship between work rate (W) and time to exhaustion (t) during intense exercise is commonly described by either a hyperbolic function (NLin), t= W'/(W-Wcp), or by its linear equivalent (LinW) Wlim=W' + Wcp(t). The parameter Wcp (critical power) has been described as an inherent characteristic of the aerobic energy system, while W' has been shown to be a ralid estimate of anaerobic work capacity. Recent studies have demonstrated that oral supplementation of creatine monohydrate (CrH2O) increases total muscle creatine stores, and have linked these increases to improved performances in intense intermittent exercise. This study was conducted to determine the effect of CrH2O supplementation on estimates of W' and Wcp derived from the NLin and LinW equations, and to determine the effect of CrH2O on t in exhaustive constant power exercise of different intensities. Fifteen active but untrained university students completed three phases of testing on a cycle ergometer: (1) familiarization, three learning trials, (2) baseline determination of W' and Wcp, four bouts performed at a W selected to elicit fatigue in 90-600 s, and (3) experimental determination of W' and Wcp, four bouts performed at the same W as baseline, but performed after 5 days of ingesting either a placebo (4 x 6 g of glucose/day) or CrH2O (4 x 5 g of CrH2O and 1 g glucose/day). Testing was administered in a double-blind manner. Analyses of covariance revealed a significant effect for CrH2O on both estimates of W' (NLin, P=0.04; LinW, P < 0.01), but not on estimates of Wcp (NLin, P=0.37; LinW; P=0.30). Within groups, t was significantly different for only CrH2O at the two highest Ws (P=0.04). It is concluded that oral ingestion of CrH2O increases estimates of W' due to an improved t at the shorter, more intense exercise bouts. Southwestern University, Department of Kinesiology, Georgetown, TX 78627, USA.

  Smith J and Wilder RP (1999). Musculoskeletal rehabilitation and sports medicine. 4. Miscellaneous sports medicine topics. Arch Phys Med Rehabil. 80 (5 Suppl 1): S68-89. Summary: This self-directed learning module highlights new advances in this topic area. It is part of the chapter on musculoskeletal rehabilitation and sports medicine in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article discusses physiatric duties as a team physician, preparticipation physical examinations, ergogenic aids, heat-related illness, pediatric sports injuries, female sports injuries, and sports medicine topics pertinent to geriatric and physically or mentally challenged athletes. New advances covered in this section include use of creatine, guidelines for the preparticipation examination, sudden cardiac athletic death, pediatric and female anterior cruciate ligament injuries, the female athlete triad, spine screening in Down syndrome athletes, and "boosting" in athletes with spinal cord injury. Mayo Clinic, Rochester, MN 55905, USA.

  Stahl CA, Allee GL and Berg EP (2001). Creatine monohydrate supplemented in swine finishing diets and fresh pork quality: II. Commercial applications. J Anim Sci. 79 (12): 3081-6. Summary: The objectives of this study were to determine the value of supplementing creatine monohydrate (CMH) in a complete swine finishing ration and determining its effects on meat quality. Crossbred barrows (n = 59) were allotted five pens per treatment with three pigs per pen. Dietary treatments, including 20 g CMH x pig(-1) x d(-1) fed for 5, 10, or 15 d before slaughter, were compared to control pigs that received no CMH. The basal diet was a corn-soybean meal finishing diet. At 123.5 kg, pigs were delivered to a commercial packing plant (80 km) and slaughtered according to industry practices. After a 24-h chill at 4 degrees C, right-side loins were collected from the fabrication line and vacuum-packaged for delivery to the University of Missouri Meat Lab. Hams were scanned for lean content by a primal cut electromagnetic scanner. After scanning, ham pH and light reflectance (L*, a*, b*) were obtained on the gluteus medius muscle. Loin pH and light reflectance were obtained at the 10/11th-rib juncture. The posterior section of the boneless loin was weighed, vacuum-packaged, and stored for 7 d at 1 degree C. After aging, light reflectance, weights, and Warner/Bratzler shear force measurements were taken. A linear trend (P = 0.071) was observed for ham 24-h L* values, and a cubic trend was observed for ultimate loin pH (P = 0.102). Hunter L* values of the longissimus possessed a negative linear contrast (P = 0.009) after aging, revealing that the loins of those animals treated for 10 and 15 d exhibit higher L* values. A cubic trend (P = 0.057) was shown for percentage of moisture lost as purge; 5- and 10-d treatments were intermediate to control and 15-d treatments. Warner/Bratzler shear force measurements for chops aged 7 d increased in a linear fashion (P = 0.024). This data suggests that 5-d supplementation of CMH before slaughter improves several pork quality attributes. However, it seems that supplementing CMH in swine diets for 10 or 15 d could reduce the quality of fresh pork. Department of Animal Science, University of Missouri, Columbia 65211, USA.

  Stockler S, Hanefeld F and Frahm J (1996). Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism. Lancet. 348 (9030): 789-90. Summary: BACKGROUND: The creatine/creatine-phosphate system is essential for the storage and transmission of phosphate-bound energy in muscle and brain. In infants, inefficiency or failure of this metabolic pathway can impair the development of motor control and mentation. METHODS: We studied and treated an infant with extrapyramidal signs who was shown--by assay for urinary creatinine and by analysis of brain metabolites with use of nuclear magnetic resonance spectra--to have depletion of body and brain creatine, due to inborn deficiency of guanidinoacetate methyltransferase (GAMT). FINDINGS: Long-term oral administration of creatine-monohydrate (4-8 g per day) to this index patient resulted in substantial clinical improvement, disappearance of magnetic resonance (MRI) signal abnormalities in the globus pallidus, and normalisation of slow background activity on the electroencephalogram (EEG). During the 25-month treatment period, both brain and total body creatine concentrations became normal. INTERPRETATION: Oral creatine replacement has proved to be effective in one child with an inborn error of GAMT. It may well be effective in the treatment of other disorders of creatine synthesis. Department of Paediatric Neurology, University Children's Hospital, Gottingen, Germany.

  Stone MH, Sanborn K, Smith LL, O'Bryant HS, Hoke T, Utter AC, Johnson RL, Boros R, Hruby J, Pierce KC, Stone ME and Garner B (1999). Effects of in-season (5 weeks) creatine and pyruvate supplementation on anaerobic performance and body composition in American football players. Int J Sport Nutr. 9 (2): 146-65. Summary: The purpose of this investigation was to study the efficacy of two dietary supplements on measures of body mass, body composition, and performance in 42 American football players. Group CM (n = 9) received creatine monohydrate, Group P (n = 11) received calcium pyruvate, Group COM (n = 11) received a combination of calcium pyruvate (60%) and creatine (40%), and Group PL received a placebo. Tests were performed before (T1) and after (T2) the 50 week supplementation period, during which the subjects continued their normal training schedules. Compared to P and PL, CM and COM showed significantly greater increases for body mass, lean body mass, 1 repetition maximum (RM) bench press, combined 1 RM squat and bench press, and static vertical jump (SVJ) power output. Peak rate of force development for SVJ was significantly greater for CM compared to P and PL. Creatine and the combination supplement enhanced training adaptations associated with body mass/composition, maximum strength, and SVJ; however, pyruvate supplementation alone was ineffective. Exercise Science Department, Appalachian State University, Boone, NC 28608, USA.

  Stout J, Eckerson J, Ebersole K, Moore G, Perry S, Housh T, Bull A, Cramer J and Batheja A (2000). Effect of creatine loading on neuromuscular fatigue threshold. J Appl Physiol. 88 (1): 109-12. Summary: The purpose of this investigation was to determine the effect of creatine (Cr) loading on the onset of neuromuscular fatigue by monitoring electromyographic fatigue curves from the vastus lateralis muscle using the physical working capacity at the fatigue threshold (PWC(FT)) test. Using a double-blind random design, 15 women athletes [mean age 19.0 +/- 2.0 (SD) yr] from the university crew team received a placebo (n = 8; 20 g glucose) or Cr (n = 7; 5 g Cr monohydrate + 20 g glucose) four times per day for 5 consecutive days. Analysis of covariance was used to analyze the data (covaried for presupplementation PWC(FT) values). The adjusted mean postsupplementation PWC(FT) value for the Cr group (mean = 186 W) was significantly (P < 0.05) higher than that of the placebo group (mean = 155 W). These findings suggest that Cr loading may delay the onset of neuromuscular fatigue. Exercise Science Department, Creighton University, Omaha, Nebraska 68178, USA. jrstout@creighton.edu.

  Syrotuik DG, Game AB, Gillies EM and Bell GJ (2001). Effects of creatine monohydrate supplementation during combined strength and high intensity rowing training on performance. Can J Appl Physiol. 26 (6): 527-42. Summary: This study investigated the effect of creatine monohydrate (Cr) supplementation on performance and training volume in rowers. Twenty-two rowers trained with continuous and interval rowing and resistance training 4 and 2 days/week, respectively, for 6 weeks. Cr supplementation consisted of a 5-day load (0.3 g/kg(-1) x day(-1)) followed by a 5-week maintenance dose (0.03 g/kg(-1) x day(-1)) while training. Five days of Cr loading did not change body composition, repeated interval rowing performance, 2,000-m rowing times, or strength performance. Five additional weeks of training with a maintenance dose of Cr or placebo significantly improved body composition, VO2max, 2,000-m rowing times, repeated power interval performance, and strength to a similar extent in both groups. Subjects training with Cr did not perform more repetitions per set of strength exercise nor produce or maintain higher power outputs during repeated rowing sessions. Cr supplementation did not increase performance or training volume over a placebo condition in rowers that performed a combined high intensity rowing and strength program. Faculty of Physical Education and Recreation, University of Alberta, Edmonton, AB, Canada.

  Tarnopolsky MA (2000). Potential benefits of creatine monohydrate supplementation in the elderly. Curr Opin Clin Nutr Metab Care. 3 (6): 497-502. Summary: Creatine plays a role in cellular energy metabolism and potentially has a role in protein metabolism. Creatine monohydrate supplementation has been shown to result in an increase in skeletal muscle total and phosphocreatine concentration, increase fat-free mass, and enhance high-intensity exercise performance in young healthy men and women. Recent evidence has also demonstrated a neuroprotective effect of creatine monohydrate supplementation in animal models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and after ischemia. A low total and phosphocreatine concentration has been reported in human skeletal muscle from aged individuals and those with neuromuscular disorders. A few studies of creatine monohydrate supplementation in the elderly have not shown convincing evidence of a beneficial effect with respect to muscle mass and/or function. Future studies will be required to address the potential for creatine monohydrate supplementation to attenuate age-related muscle atrophy and strength loss, as well as to protect against age-dependent neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Dept of Neurology/Neurological Rehabilitation, McMaster University Medical Center, Hamilton, Ontario, Canada. tarnopol@fhs.mcmaster.ca.

  Tarnopolsky MA and MacLennan DP (2000). Creatine monohydrate supplementation enhances high-intensity exercise performance in males and females. Int J Sport Nutr Exerc Metab. 10 (4): 452-63. Summary: Creatine monohydrate supplementation has been shown to enhance high-intensity exercise performance in some but not all studies. Part of the controversy surrounding the ergogenic effect(s) of creatine monohydrate supplementation may relate to design issues that result in low statistical power. A further question that remains unresolved in the creatine literature is whether or not males and females respond in a similar manner to supplementation. We studied the effect of creatine supplementation upon high intensity exercise performance in 24 subjects (n = 12 males, n = 12 females). Creatine monohydrate (Cr; 5g, 4x/d 3 4d) and placebo (Pl; glucose polymer 3 4d) were provided using a randomized, double-blind crossover design (7 week washout). Outcome measures included: 2 3 30-s anaerobic cycle test, with plasma lactate pre- and post-test; dorsi-flexor: maximal voluntary contraction (MVC), 2-min fatigue test, and electrically stimulated peak and tetanic torque; isokinetic knee extension torque and 1-min ischemic handgrip strength. Significant main effects of Cr treatment included: increased peak and relative peak anaerobic cycling power ( 3.7%; p <. 05), dorsi-flexion MVC torque ( 6.6%; p <.05), and increased lactate ( 20.8%; p <.05) with no gender specific responses. We concluded that short-term Cr supplementation can increase indices of high-intensity exercise performance for both males and females. Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.

  Tarnopolsky M and Martin J (1999). Creatine monohydrate increases strength in patients with neuromuscular disease. Neurology. 52 (4): 854-7. Summary: Creatine monohydrate has been shown to increase strength in studies of young healthy subjects and in a few studies with patients. Creatine monohydrate (10 g daily for 5 days to 5 g daily for 5 days) was administered to patients with neuromuscular disease in a pilot study (Study 1; n = 81), followed by a single-blinded study (Study 2; n = 21). Body weight, handgrip, dorsiflexion, and knee extensor strength were measured before and after treatment. Creatine administration increased all measured indices in both studies. Short-term creatine monohydrate increased high-intensity strength significantly in patients with neuromuscular disease. Department of Neurology/Neurological Rehabilitation and Kinesiology, McMaster University Medical Center, Hamilton, Ontario, Canada. tarnopol@mcmaster.ca.

  Tarnopolsky MA and Parise G (1999). Direct measurement of high-energy phosphate compounds in patients with neuromuscular disease. Muscle Nerve. 22 (9): 1228-33. Summary: Several neuromuscular disorders are associated with reductions in intramuscular adenosine triphosphate (ATP) and/or phosphocreatine (PCr). These alterations have been primarily characterized using (31)P-magnetic resonance spectroscopy ((31)P-MRS). We prospectively measured total creatine, PCr, and ATP in muscle biopsies from 81 patients: normal controls (n = 33), mitochondrial cytopathy (n = 8), neuropathic (n = 3), dystrophy/congenital myopathies (n = 7), inflammatory myopathy (n = 12), and miscellaneous myopathies (n = 18) using direct biochemical analysis. Intramuscular concentrations of PCr and ATP were lower for the dystrophy/congenital myopathy, inflammatory myopathy, and mitochondrial disease patients with ragged red fiber (RRF) as compared with normal controls (P < 0.05). Total creatine was lower for the dystrophy/congenital myopathy group as compared with the normal control group (P < 0.05). These values compare favorably to results from other studies using (31)P-MRS and provide external validation for the values obtained using that method. Given the reductions in high-energy phosphate compounds in these patients, there is the potential for therapeutic intervention with creatine monohydrate supplementation. Department of Neurology/Neurological Rehabilitation, Rm. 4U4, McMaster University Medical Center, 1200 Main St. W., Hamilton, Ontario, Canada, L8N 3Z5.

  Tarnopolsky MA, Parise G, Yardley NJ, Ballantyne CS, Olatinji S and Phillips SM (2001). Creatine-dextrose and protein-dextrose induce similar strength gains during training. Med Sci Sports Exerc. 33 (12): 2044-52. Summary: BACKGROUND: Creatine supplementation during resistance exercise training has been reported to induce greater increases in fat-free mass (FFM), muscle fiber area, and strength when compared with a placebo. We have recently shown that timing of nutrient delivery in the postexercise period can have positive effects on whole body protein turnover (B. D. Roy et al., Med Sci Sports Exerc. 32(8):1412-1418, 2000). PURPOSE: We tested the hypothesis that a postexercise protein-carbohydrate supplement would result in similar increases in FFM, muscle fiber area, and strength as compared with creatine monohydrate (CM), during a supervised 2-month resistance exercise training program in untrained men. METHODS: Young healthy male subjects were randomized to receive either CM and glucose (N = 11; CM 10 g + glucose 75 g [CR-CHO] (CELL-Tech)) or protein and glucose (N = 8; casein 10 g + glucose 75 g [PRO+CHO]), using double-blinded allocation. Participants performed 8 wk of whole body split-routine straight set weight training, 1 h.d(-1), 6 d.wk(-1). Measurements, pre- and post-training were made of fat-free mass (FFM; DEXA), total body mass, muscle fiber area, isokinetic knee extension strength (45 and 240 degrees.s(-1)), and 1 repetition maximal (1RM) strength for 16 weight training exercises. RESULTS: Total body mass increased more for CR-CHO (+4.3 kg, 5.4%) as compared with PRO-CHO (+1.9 kg, 2.4%) (P < 0.05 for interaction) and FFM increased after training (P < 0.01) but was not significantly different between the groups (CR-CHO = +4.0 kg, 6.4%; PRO-CHO = +2.6 kg, 4.1%) (P = 0.11 for interaction). Muscle fiber area increased similarly after training for both groups (approximately 20%; P < 0.05). Training resulted in an increase in 1RM for each of the 16 activities (range = 14.2-39.9%) (P < 0.001), isokinetic knee extension torque (P < 0.01), with no treatment effects upon any of the variables. CONCLUSIONS: We concluded that postexercise supplementation with PRO-CHO resulted in similar increases in strength after a resistance exercise training program as compared with CR-CHO. However, the greater gains in total mass for the CR-CHO group may have implications for sport-specific performance. Department of Medicine (Neurology and Neurological Rehabilitation), Rm. 4U4, McMaster University Medical Center, 1200 Main Street W., Hamilton, Ontario, Canada, L8N 3Z5. tarnopol@mcmaster.ca.

  Tarnopolsky MA, Roy BD and MacDonald JR (1997). A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve. 20 (12): 1502-9. Summary: Fatigue in patients with mitochondrial cytopathies is associated with decreased basal and postactivity muscle phosphocreatine (PCr). Creatine monohydrate supplementation has been shown to increase muscle PCr and high-intensity power output in healthy subjects. We studied the effects of creatine monohydrate administration (5 g PO b.i.d. x 14 days --> 2 g PO b.i.d. x 7 days) in 7 mitochondrial cytopathy patients using a randomized, crossover design. Measurements included: activities of daily living (visual analog scale); ischemic isometric handgrip strength (1 min); basal and postischemic exercise lactate; evoked and voluntary contraction strength of the dorsiflexors; nonischemic, isometric, dorsiflexion torque (NIDFT, 2 min); and aerobic cycle ergometry with pre- and post-lactate measurements. Creatine treatment resulted in significantly (P < 0.05) increased handgrip strength, NIDFT, and postexercise lactate, with no changes in the other measured variables. We concluded that creatine monohydrate increased the strength of high-intensity anaerobic and aerobic type activities in patients with mitochondrial cytopathies but had no apparent effects upon lower intensity aerobic activities. Department of Neurology, McMaster University Medical Center, Hamilton, Ontario, Canada.

  Terjung RL, Clarkson P, Eichner ER, Greenhaff PL, Hespel PJ, Israel RG, Kraemer WJ, Meyer RA, Spriet LL, Tarnopolsky MA, Wagenmakers AJ and Williams MH (2000). American College of Sports Medicine roundtable. The physiological and health effects of oral creatine supplementation. Med Sci Sports Exerc. 32 (3): 706-17. Summary: Creatine (Cr) supplementation has become a common practice among professional, elite, collegiate, amateur, and recreational athletes with the expectation of enhancing exercise performance. Research indicates that Cr supplementation can increase muscle phosphocreatine (PCr) content, but not in all individuals. A high dose of 20 g x d(-1) that is common to many research studies is not necessary, as 3 g x d(-1) will achieve the same increase in PCr given time. Coincident ingestion of carbohydrate with Cr may increase muscle uptake; however, the procedure requires a large amount of carbohydrate. Exercise performance involving short periods of extremely powerful activity can be enhanced, especially during repeated bouts of activity. This is in keeping with the theoretical importance of an elevated PCr content in skeletal muscle. Cr supplementation does not increase maximal isometric strength, the rate of maximal force production, nor aerobic exercise performance. Most of the evidence has been obtained from healthy young adult male subjects with mixed athletic ability and training status. Less research information is available related to the alterations due to age and gender. Cr supplementation leads to weight gain within the first few days, likely due to water retention related to Cr uptake in the muscle. Cr supplementation is associated with an enhanced accrual of strength in strength-training programs, a response not independent from the initial weight gain, but may be related to a greater volume and intensity of training that can be achieved. There is no definitive evidence that Cr supplementation causes gastrointestinal, renal, and/or muscle cramping complications. The potential acute effects of high-dose Cr supplementation on body fluid balance has not been fully investigated, and ingestion of Cr before or during exercise is not recommended. There is evidence that medical use of Cr supplementation is warranted in certain patients (e.g.. neuromuscular disease); future research may establish its potential usefulness in other medical applications. Although Cr supplementation exhibits small but significant physiological and performance changes, the increases in performance are realized during very specific exercise conditions. This suggests that the apparent high expectations for performance enhancement, evident by the extensive use of Cr supplementation, are inordinate. Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia 65211, USA. TerjungR@missouri.edu.

  Terrillion KA, Kolkhorst FW, Dolgener FA and Joslyn SJ (1997). The effect of creatine supplementation on two 700-m maximal running bouts. Int J Sport Nutr. 7 (2): 138-43. Summary: We investigated the effect of creatine supplementation on maximal running performance in a simulated track competition. Twelve competitive male runners were assigned to either a placebo or creatine supplementation group. Both groups completed two maximal 700-m running bouts 60 min apart on an outdoor track. A second identical trial was performed 7 days later, and for 5 days prior to the second trial, subjects ingested 20 g.day-1 of either creatine monohydrate or a placebo. Subjects in the placebo group ran 110.2 +/- 3.5 s and 110.4 +/- 3.0 s for the first trial and 108.5 +/- 2.9 s and 108.0 +/- 1.7 s for the second trial, while the creatine group ran 109.9 +/- 3.2 s and 110.4 +/- 3.6 s for the first trial and 109.7 +/- 3.3 s and 107.8 +/- 2.2 s for the second trial. There were no significant differences between groups by trial or Trial X Time for running time, postexercise blood lactate concentration, or body weight (p > .05). We concluded that creatine supplementation does not enhance performance of single or twice-repeated maximal running bouts lasting 90-120 s. School of Health, University of Northern Iowa, Cedar Falls 50614-0241, USA.

  Urbanski RL, Vincent WJ and Yaspelkis BB, 3rd (1999). Creatine supplementation differentially affects maximal isometric strength and time to fatigue in large and small muscle groups. Int J Sport Nutr. 9 (2): 136-45. Summary: Ten physically active, untrained, college-aged males (26.4 +/- 5. 8 years old) received creatine (CR, 5 g creatine monohydrate + 3 g dextrose) and placebo (PLA, 7 g dextrose) supplementation four times per day for 5 days in a double-blind, randomized, balanced, crossover design. Performance was assessed during maximal and three repeated submaximal bouts of isometric knee extension and handgrip exercise. CR supplementation significantly increased (p <.05) maximal isometric strength during knee extension but not during handgrip exercise. CR supplementation increased time to fatigue during each of the three bouts of submaximal knee extension and handgrip exercise when compared to the PLA trials. These findings suggest that CR supplementation can increase maximal strength and time to fatigue during isometric exercise. However, the improvements in maximal isometric strength following CR supplementation appear to be restricted to movements performed with a large muscle mass. Exercise Biochemistry Laboratory, Department of Kinesiology, California State University - Northridge, 18111 Nordhoff Street, Northridge, CA 91330-8287, USA.

  Vandebuerie F, Vanden Eynde B, Vandenberghe K and Hespel P (1998). Effect of creatine loading on endurance capacity and sprint power in cyclists. Int J Sports Med. 19 (7): 490-5. Summary: The effect of creatine loading on endurance capacity and sprint performance was investigated in elite cyclists according to a double-blind cross-over study design. Subjects (n = 12) underwent on 3 occasions and separated by 5 week wash-out periods, a 2 h 30 min standardized endurance protocol on their own race bicycle, which was mounted on an electromagnetically braked roller-system, whereupon they cycled to exhaustion at their predetermined 4 mmol lactate threshold. Immediately thereafter they performed 5 maximal 10 second sprints, separated by 2 min recovery intervals, on a Monark bicycle ergometer at 6 kg resistance on the flywheel. Before the exercise test, subjects were either creatine loaded (C: 25 g creatine monohydrate/day, 5 days) or were creatine loaded plus ingested creatine during the exercise test (CC: 5 g/h), or received placebo (P). Compared with P, C but not CC increased (p<0.05) peak and mean sprint power output by 8-9% for all 5 sprints. Endurance time to exhaustion was not affected by either C or CC. It is concluded that creatine loading improves intermittent sprint capacity at the end of endurance exercise to fatigue. This ergogenic action is counteracted by high dose creatine intake during exercise. Faculty of Physical Education and Physiotherapy, Department of Kinesiology, Katholieke Universiteit Leuven, Belgium.

  van Leemputte M, Vandenberghe K and Hespel P (1999). Shortening of muscle relaxation time after creatine loading. J Appl Physiol. 86 (3): 840-4. Summary: The effect of creatine (Cr) supplementation on muscle isometric torque generation and relaxation was investigated in healthy male volunteers. Maximal torque (Tmax), contraction time (CT) from 0.25 to 0.75 of Tmax, and relaxation time (RT) from 0.75 to 0.25 of Tmax were measured during 12 maximal isometric 3-s elbow flexions interspersed by 10-s rest intervals. Between the pretest and the posttest, subjects ingested Cr monohydrate (4 x 5 g/day; n = 8) or placebo (n = 8) for 5 days. Pretest Tmax, CT, and RT were similar in Cr and placebo groups. Also in the posttest, Tmax and CT were similar between groups. However, posttest RT was decreased consistently by approximately 20% (P < 0.05) in the Cr group from the first to the last of the 12 contractions. In addition, the mean decrease in RT after Cr loading was positively correlated with pretest RT (r = 0.82). It is concluded that Cr loading facilitates the rate of muscle relaxation during brief isometric muscle contractions without affecting torque production. Department of Kinesiology, Faculty of Physical Education and Physiotherapy, Katholieke Universiteit Leuven, B-3001 Leuven, Belgium.

  van der Knaap MS, Verhoeven NM, Maaswinkel-Mooij P, Pouwels PJ, Onkenhout W, Peeters EA, Stockler-Ipsiroglu S and Jakobs C (2000). Mental retardation and behavioral problems as presenting signs of a creatine synthesis defect. Ann Neurol. 47 (4): 540-3. Summary: Recently, 3 patients with a creatine synthesis defect have been described. They presented with developmental regression, extrapyramidal movement abnormalities, and intractable epilepsy, and they improved with treatment of creatine monohydrate. We report 2 unrelated boys with a creatine synthesis defect and nonspecific presenting signs of psychomotor retardation, behavioral problems, and, in 1, mild epilepsy. Metabolic urine screening revealed elevations in all metabolites, expressed as millimoles per mole of creatinine, which suggests decreased creatinine excretion. This finding led to the correct diagnosis. We propose to include the assessment of the overall concentrations of amino acids and organic acids relative to creatinine in routine metabolic urine screening. Department of Child Neurology, Free University Hospital, Amsterdam, The Netherlands.

  Volek JS, Duncan ND, Mazzetti SA, Putukian M, Gomez AL and Kraemer WJ (2000). No effect of heavy resistance training and creatine supplementation on blood lipids. Int J Sport Nutr Exerc Metab. 10 (2): 144-56. Summary: In order to examine the effects of heavy resistance training and the influence of creatine supplementation on nonperformance measures of health status, 19 healthy resistance-trained men were matched and then randomly assigned in a double-blind fashion to either a creatine (n = 10) or placebo (n = 9) group. Periodized heavy resistance training was performed 3-4 times per week for 12 weeks. During the first week of training, creatine subjects consumed 25 g creatine monohydrate per day, while the placebo group ingested an equal number of placebo capsules. Five grams of supplement per day was consumed for the remainder of the study. Body composition, fasting serum creatinine, lipoproteins and triglycerides, and reported changes in body function were determined prior to and after 12 weeks of training and supplementation. After training, significant increases in body mass and fat-free mass were greater in creatine (5.2 and 4.3 kg, respectively) than placebo (3.0 and 2.1 kg, respectively) subjects. There was no change in percent body fat. Dietary energy and macronutrient distribution was not significantly different during Weeks 1 and 12. Serum creatinine was significantly elevated in creatine subjects after 1 (11.6%) and 12 weeks (13.8%); however, values were within normal limits for healthy men. There were no effects of training or supplementation on serum total cholesterol, HDL-cholesterol, LDL-cholesterol, or triglycerides. In healthy men, a 12-week heavy resistance training program, with or without creatine supplementation, did not significantly influence serum lipid profiles, subjective reports of body functioning, or serum creatinine concentrations. Human Performance Laboratory, Ball State University, Muncie, IN 47306, USA.

  Volek JS, Kraemer WJ, Bush JA, Boetes M, Incledon T, Clark KL and Lynch JM (1997). Creatine supplementation enhances muscular performance during high-intensity resistance exercise. J Am Diet Assoc. 97 (7): 765-70. Summary: OBJECTIVE: This study was undertaken to investigate the influence of oral supplementation with creatine monohydrate on muscular performance during repeated sets of high-intensity resistance exercise. SUBJECTS/DESIGN: Fourteen active men were randomly assigned in a double-blind fashion to either a creatine group (n = 7) or a placebo group (n = 7). Both groups performed a bench press exercise protocol (5 sets to failure using each subject's predetermined 10-repetition maximum) and a jump squat exercise protocol (5 sets of 10 repetitions using 30% of each subject's 1-repetition maximum squat) on three different occasions (T1, T2, and T3) separated by 6 days. INTERVENTION: Before T1, both groups received no supplementation. From T1 to T2, both groups ingested placebo capsules. From T2 to T3, the creatine group ingested 25 g creatine monohydrate per day, and the placebo group ingested an equivalent amount of placebo. MAIN OUTCOME MEASURES: Total repetitions for each set of bench presses and peak power output for each set of jump squats were determined. Other measures included assessment of diet, body mass, skinfold thickness, and preexercise and 5-minute postexercise lactate concentrations. RESULTS: Lifting performance was not altered for either exercise protocol after ingestion of the placebos. Creatine supplementation resulted in a significant improvement in peak power output during all 5 sets of jump squats and a significant improvement in repetitions during all 5 sets of bench presses. After creatine supplementation, postexercise lactate concentrations were significantly higher after the bench press but not the jump squat. A significant increase in body mass of 1.4 kg (range = 0.0 to 2.7 kg) was observed after creatine ingestion. CONCLUSION: One week of creatine supplementation (25 g/day) enhances muscular performance during repeated sets of bench press and jump squat exercise. Center for Sports Medicine, Pennsylvania State University, University Park 16802, USA.

  Volek JS, Mazzetti SA, Farquhar WB, Barnes BR, Gomez AL and Kraemer WJ (2001). Physiological responses to short-term exercise in the heat after creatine loading. Med Sci Sports Exerc. 33 (7): 1101-8. Summary: PURPOSE: This investigation was designed to examine the influence of creatine (Cr) supplementation on acute cardiovascular, renal, temperature, and fluid-regulatory hormonal responses to exercise for 35 min in the heat. METHODS: Twenty healthy men were matched and then randomly assigned to consume 0.3 g.kg(-1) Cr monohydrate (N = 10) or placebo (N = 10) for 7 d in a double-blind fashion. Before and after supplementation, both groups cycled for 30 min at 60-70% VO2(peak) immediately followed by three 10-s sprints in an environmental chamber at 37 degrees C and 80% relative humidity. RESULTS: Body mass was significantly increased (0.75 kg) in Cr subjects. Heart rate, blood pressure, and sweat rate responses to exercise were not significantly different between groups. There were no differences in rectal temperature responses in either group. Sodium, potassium, and creatinine excretion rates obtained from 24-h and exercise urine collection periods were not significantly altered in either group. Serum creatinine was elevated in the Cr group but within normal ranges. There were significant exercise-induced increases in cortisol, aldosterone, renin, angiotensin I and II, atrial peptide, and arginine vasopressin. The aldosterone response was slightly greater in the Cr (263%) compared with placebo (224%) group. Peak power was greater in the Cr group during all three 10-s sprints after supplementation and unchanged in the placebo group. There were no reports of adverse symptoms, including muscle cramping during supplementation or exercise. CONCLUSION: Cr supplementation augments repeated sprint cycle performance in the heat without altering thermoregulatory responses. The Human Performance Laboratory, Ball State University, Muncie, IN 47306, USA. jvolek@bsu.edu.

  Vona-Davis L, Wearden PD, Karne NH and Hill RC (2002). Effect of creatine monohydrate on cardiac function in a rat model of endotoxemia. J Surg Res. 103 (1): 1-7. Summary: BACKGROUND: Reports have attributed cardiac failure during acute models of endotoxemia to a lack of high-energy phosphates. This study was undertaken to investigate whether creatine (Cr) administered during perfusion could enhance myocardial protection and improve recovery of cardiac function in a rat model of endotoxemia. METHODS: Acute endotoxemia was induced in rats by a bolus injection of Escherichia coli endotoxin (LPS: 4 mg/kg, ip) while control rats were injected with an equal volume of 0.9% normal saline. To assess the adequacy of energy metabolism, freeze-clamped hearts were obtained from animals to study the concentrations of endogenous ATP, phosphocreatine (PCr), inorganic phosphate (P(i)), and intracellular pH by (31)P-cryomagnetic resonance spectroscopy. In a separate experiment, isolated hearts were perfused via a Langendorff column with Krebs-Henseleit buffer containing different concentrations of creatine monohydrate (1, 3, or 10 mM). Cardiac performance was evaluated via a paced (300 bpm) isovolumetric balloon preparation. Measurements of cardiac function including left ventricular developed pressure (LVDP), the maximum rates of ventricular pressure rise (LV +dP/dt) and fall (LV -dP/dt), and coronary flow were made for both LPS and saline-treated animals. RESULTS: High-energy phosphate ratios of PCr/ATP and PCr/P(i) in hearts declined significantly at 4 h after endotoxin treatment. As anticipated, LVDP and LV +dP/dt(max) at a given preload and heart rate were significantly (P < 0.05) lower at 4 h when measured at the same time point. The functional recovery of these parameters was not improved by the addition of creatine monohydrate to the perfusion buffer. Creatine produced a significant (P < 0.05) negative inotropic effect in hearts from saline-treated animals. The LVDP was reduced by 30% at the lowest concentration and by 50% at the highest concentration of creatine monohydrate. Furthermore, creatine significantly (P < 0.05) reduced LV -dP/dt(max) in both saline and LPS-treated rats. These data demonstrate that exogenous creatine does not contribute to myocardial preservation in endotoxemia. CONCLUSIONS: Energy stores in the rat heart decline early in endotoxemia accompanied by reduced myocardial performance, suggesting that the ability of the heart to perform mechanical work is impaired. Cardiac dysfunction in an acute model of endotoxemia was not improved with exogenous creatine during perfusion. Creatine's effects were primarily lusitropic by delaying the onset of myocardial relaxation in all hearts. The deleterious effects of exogenous creatine monohydrate in normal hearts should be examined in future experimental studies. Department of Surgery, West Virginia University, Morgantown, West Virginia 26506, USA. lvdavis@hsc.wvu.edu.

  Vorgerd M, Grehl T, Jager M, Muller K, Freitag G, Patzold T, Bruns N, Fabian K, Tegenthoff M, Mortier W, Luttmann A, Zange J and Malin JP (2000). Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial. Arch Neurol. 57 (7): 956-63. Summary: OBJECTIVE: To determine whether treatment with creatine can improve exercise intolerance in myophosphorylase deficiency (McArdle disease). DESIGN: Double-blind, placebo-controlled crossover study with oral creatine monohydrate supplementation. PATIENTS: Nine patients with biochemically and genetically proven McArdle disease were treated. INTERVENTION: Five days of daily high-dose creatine intake (150 mg/kg body weight) were followed by daily low-dose creatine intake (60 mg/kg). Each treatment phase with creatine or placebo lasted 5 weeks. MAIN OUTCOME MEASURES: The effect of treatment was estimated at the end of each treatment phase by recording clinical scores, ergometer exercise test results, phosphorus 31 nuclear magnetic resonance spectroscopy, and surface electromyography. RESULTS: Of 9 patients, 5 reported improvement of muscle complaints with creatine. Force-time integrals (P =.03) and depletion of phosphocreatine (P =.04) increased significantly during ischemic exercise with creatine. Phosphocreatine depletion also increased significantly during aerobic exercise (P =.006). The decrease of median frequency in surface electromyograms during contraction was significantly larger (P =.03) with creatine. CONCLUSION: This is the first controlled study indicating that creatine supplementation improves skeletal muscle function in McArdle disease. Department of Neurology, Ruhr-University Bochum, Kliniken Bergmannsheil, Burkle-de-la-Camp-Platz 1, 44789 Bochum, Germany. matthias.vorgerd@ruhr-uni-bochum.de.

  Walter MC, Lochmuller H, Reilich P, Klopstock T, Huber R, Hartard M, Hennig M, Pongratz D and Muller-Felber W (2000). Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study. Neurology. 54 (9): 1848-50. Summary: The authors assessed the safety and efficacy of creatine monohydrate (Cr) in various types of muscular dystrophies in a double-blind, crossover trial. Thirty-six patients (12 patients with facioscapulohumeral dystrophy, 10 patients with Becker dystrophy, 8 patients with Duchenne dystrophy, and 6 patients with sarcoglycan-deficient limb girdle muscular dystrophy) were randomized to receive Cr or placebo for 8 weeks. There was mild but significant improvement in muscle strength and daily-life activities by Medical Research Council scales and the Neuromuscular Symptom Score. Cr was well tolerated throughout the study period. Friedrich-Baur-Institute, Ludwig-Maximilians-University of Munich, Germany. Maggie.Walter@lrz.uni-muenchen.de.

  Wick M, Fujimori H, Michaelis T and Frahm J (1999). Brain water diffusion in normal and creatine-supplemented rats during transient global ischemia. Magn Reson Med. 42 (4): 798-802. Summary: Brain water diffusion in response to transient global ischemia (12 min), reperfusion (60 min), and cardiac arrest was monitored by localized proton magnetic resonance spectroscopy. The trace of the apparent diffusion coefficient tensor (ADC(Av)) was determined at high temporal resolution (10 sec) to assess the putative neuroprotective potential of oral creatine (Cr) in rats that received 2.2 g Cr-monohydrate per kg body weight per day for 10 days (n = 8) relative to controls (n = 9). Cr-fed rats revealed a statistically significant increase of the cerebral concentration ratio of Cr to choline-containing compounds (20%). The decrease of the ADC(Av) value during acute ischemia showed a three-phasic behavior in line with energy depletion, cytotoxic edema, and brain cooling. In Cr-fed rats, slightly less severe and mildly delayed diffusion changes during ischemia and similar beneficial trends during early reperfusion did not reach statistical significance. Magn Reson Med 42:798-802, 1999. Biomedizinische NMR Forschungs GmbH am, Max-Planck-Institut fur biophysikalische Chemie, Gottingen, Germany.

  Wiedermann D, Schneider J, Fromme A, Thorwesten L and Moller HE (2001). Creatine loading and resting skeletal muscle phosphocreatine flux: a saturation-transfer NMR study. Magma. 13 (2): 118-26. Summary: 31P saturation-transfer nuclear magnetic resonance spectroscopy was used to study skeletal muscle phosphocreatine (PCr) flux in healthy male volunteers. Data analysis included consideration of effects from incomplete saturation and radiofrequency spillover. Spectra were recorded from the resting gastrocnemius muscle before and after 6 days of creatine monohydrate (Cr-H2O) intake (20 g/day). Parallel to an improved muscle performance during maximal intermittent exercise following Cr-H2O supplementation, the concentration of PCr increased (P=0.01) by 23% (34.9+/-2.8 mmol/l vs. 28.6+/-2.7 mmol/l), whereas other metabolites were unaffected (inorganic phosphate: 4.3+/-1.4 mmol/l, free intracellular Mg(2+): 1.1+/-0.7 mmol/l, cytosolic pH: 7.04+/-0.02). Forward and reverse fluxes through the creatine kinase (CK) reaction did not change significantly from their baseline levels (v(for): 11.8+/-5.4 mmol/l per second vs. 15.3+/-6.8 mmol/l per second, (v(rev): 9.5+/-3.4 mmol/l per second vs. 10.9+/-3.7 mmol/l per second). The rate of PCr resynthesis in resting muscle is not limited by the CK reaction, which is near equilibrium. Consequently, the post-load increase in total creatine has no effect on the unidirectional CK reaction rates. Institut fur Physikalische Chemie, Westfalische Wilhelms-Universitat Munster, Schlossplatz 4/7, D-48149, Munster, Germany.

  Wilken B, Ramirez JM, Probst I, Richter DW and Hanefeld F (2000). Anoxic ATP depletion in neonatal mice brainstem is prevented by creatine supplementation. Arch Dis Child Fetal Neonatal Ed. 82 (3): F224-7. Summary: BACKGROUND: Sufficient ATP concentrations maintain physiological processes and protect tissue from hypoxic damage. With decreasing oxygen concentration, ATP synthesis relies increasingly on the presence of phosphocreatine. AIM: The effect of exogenously applied creatine on phosphocreatine and ATP concentrations was studied under control and anoxic conditions. METHODS: Pregnant mice were fed orally with creatine monohydrate (2 g/kg body weight/day). Brainstem slices from these mice pups were compared with those from pups of non-creatine supplemented pregnant mice. Measurements were performed under normoxic and anoxic conditions. In addition, brainstem slices from non-creatine treated mice pups were incubated for 3 hours in control artificial cerebrospinal fluid (CSF) (n = 10) or in artificial CSF containing 200 microM creatine (n = 10). ATP and phosphocreatine contents were determined enzymatically in single brainstem slices. RESULTS: ATP concentrations were in the same range in all preparations. However, there was a significant increase of phosphocreatine in the brainstems from pups of creatine fed mice when compared with the brainstems of pups from non-creatine treated mice or in non-incubated brainstems of control animals. After 30 minutes anoxia, ATP as well as phosphocreatine concentrations remained significantly higher in creatine pretreated slices compared with controls. CONCLUSION: The data indicate that exogenous application of creatine is effective in neuroprotection. Klinik fur Padiatrie und Neuropadiatrie, Universitat Gottingen, 37075 Gottingen, Germany.

  Willer B, Stucki G, Hoppeler H, Bruhlmann P and Krahenbuhl S (2000). Effects of creatine supplementation on muscle weakness in patients with rheumatoid arthritis. Rheumatology (Oxford). 39 (3): 293-8. Summary: BACKGROUND AND OBJECTIVES: Patients with rheumatoid arthritis (RA) frequently suffer from muscle weakness. Oral administration of creatine has been shown to improve muscle strength in healthy subjects. The objective of this study was to examine the effect of oral creatine supplementation on muscle weakness, disease activity and activities of daily living in patients with RA. METHODS: During a period of 3 weeks, 12 patients with RA were treated with creatine monohydrate (20 g/day for 5 days followed by 2 g/day for 16 days). They were examined on entry and at the end of the study. The patients were investigated clinically, blood and urine samples were obtained, muscle biopsies were performed before and after treatment, muscle strength was determined, and self-administered patient questionnaires were completed. RESULTS: From all patients we were able to obtain full clinical and questionnaire data, while biopsies were taken from 12 patients at the start and from nine patients at the end of the study. Muscle strength, as determined by the muscle strength index, increased in eight of 12 patients. In contrast, physical functional ability and disease activity did not change significantly. The creatine concentration in serum and skeletal muscle increased significantly, while creatine phosphate and total creatine did not increase in skeletal muscle. The skeletal muscle creatine content was associated with muscle strength at baseline but not after administration of creatine. The changes in muscle strength were not associated with the changes in skeletal muscle creatine or creatine phosphate. CONCLUSION: Although the skeletal muscle creatine content and muscle strength increased with creatine administration in some patients with RA, a clear clinical benefit could not be demonstrated for this treatment when the patients were considered as one group. Department of Rheumatology and Physical Medicine, University Hospital of Zurich, Switzerland.

  Williams MH and Branch JD (1998). Creatine supplementation and exercise performance: an update. J Am Coll Nutr. 17 (3): 216-34. Summary: Creatine, a natural nutrient found in animal foods, is alleged to be an effective nutritional ergogenic aid to enhance sport or exercise performance. Research suggests that oral creatine monohydrate supplementation may increase total muscle creatine [TCr], including both free creatine [FCr] and phosphocreatine [PCr]. Some, but not all, studies suggest that creatine supplementation may enhance performance in high-intensity, short-term exercise tasks that are dependent primarily on PCr (i.e., < 30 seconds), particularly laboratory tests involving repeated exercise bouts with limited recovery time between repetitions; additional corroborative research is needed regarding its ergogenic potential in actual field exercise performance tasks dependent on PCr. Creatine supplementation has not consistently been shown to enhance performance in exercise tasks dependent on anaerobic glycolysis, but additional laboratory and field research is merited. Additionally, creatine supplementation has not been shown to enhance performance in exercise tasks dependent on aerobic glycolysis, but additional research is warranted, particularly on the effect of chronic supplementation as an aid to training for improvement in competitive performance. Short-term creatine supplementation appears to increase body mass in males, although the initial increase is most likely water. Chronic creatine supplementation, in conjunction with physical training involving resistance exercise, may increase lean body mass. However, confirmatory research data are needed. Creatine supplementation up to 8 weeks has not been associated with major health risks, but the safety of more prolonged creatine supplementation has not been established. Creatine is currently legal and its use by athletes is not construed as doping. Department of Exercise Science, Physical Education, and Recreation, Old Dominion University, Norfolk, Virginia 23529-0196, USA.

  Wyss M and Kaddurah-Daouk R (2000). Creatine and creatinine metabolism. Physiol Rev. 80 (3): 1107-213. Summary: The goal of this review is to present a comprehensive survey of the many intriguing facets of creatine (Cr) and creatinine metabolism, encompassing the pathways and regulation of Cr biosynthesis and degradation, species and tissue distribution of the enzymes and metabolites involved, and of the inherent implications for physiology and human pathology. Very recently, a series of new discoveries have been made that are bound to have distinguished implications for bioenergetics, physiology, human pathology, and clinical diagnosis and that suggest that deregulation of the creatine kinase (CK) system is associated with a variety of diseases. Disturbances of the CK system have been observed in muscle, brain, cardiac, and renal diseases as well as in cancer. On the other hand, Cr and Cr analogs such as cyclocreatine were found to have antitumor, antiviral, and antidiabetic effects and to protect tissues from hypoxic, ischemic, neurodegenerative, or muscle damage. Oral Cr ingestion is used in sports as an ergogenic aid, and some data suggest that Cr and creatinine may be precursors of food mutagens and uremic toxins. These findings are discussed in depth, the interrelationships are outlined, and all is put into a broader context to provide a more detailed understanding of the biological functions of Cr and of the CK system. F. Hoffmann-La Roche, Vitamins and Fine Chemicals Division, Basel, Switzerland. markus.wyss@roche.com.  

©Wise Young PhD, MD

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