Creatine and its Application as an Ergogenic Aid

Transcription

1 International Journal of Sport Nutrition, 1995, 5, S1 00-St 10 O 1995 Human Kinetics Publishers, Inc. Creatine and its Application as an Ergogenic Aid Paul 1. Greenhaff Phosphwreatine (PCr) availability is likely to limit performance in brief, high-power exercise because the depletion of PCr results in an inability to maintain adenosine triphosphate (ATP) resynthesis at the rate required. It is now known that the daily ingestion of four 5-g doses of creatine for 5 days will significantly increase intramuscular creatine and PCr concentrations prior to exercise and will facilitate PCr resynthesis during recovery from exercise, particularly in those individuals with relatively low creatine concentrations prior to feedimg. As a consequence of matine ingestion, work output during repeated bouts of high-power exercise has been increased under a variety of experimental conditions. The reduced accumulation of ammonia and hypoxanthine in plasma and the attenuation of muscle ATP degradation after creatine feeding suggest that the ergogenic effect of creatine is achieved by better maintaining ATP turnover during contraction. Creatine was first identified by Chevreul in 1835 in meat extract; in 1847, Liebig showed that creatine could be extracted from several kinds of muscle but not from the other organs he investigated. During the following years, whether or not the creatine concentration of muscle increased during contraction was debated. However, shortly before the discovery of phosphocreatine (PCr) by Fiske and Subbarow between 1927 and 1929, Schlossmann and Tiegs showed that "diffusible" creatine increased during contraction (for further information see Needham [26]). Thus, even early in this century there was literature indicating an important function for creatine in muscle contraction and awareness of its fairly specific distribution and its absence from normal urine, leading to the realization that it was not merely a by-product of metabolism (for further information see Hunter [20, 211). This realization was confiied when Chanutin (9) observed that a major portion of ingested creatine was retained by the body. Since this time, much work has been devoted to understanding the biosynthesis and metabolism of creatine and the excretion of its breakdown product, creatinine. In addition to being present in the diet, creatine is endogenously synthesized by the liver and pancreas in humans (32). However, because 95% of the body creatine pool is found in skeletal muscle, creatine must be transported from its sites of synthesis to skeletal muscle. Indeed, little creatine is found in the major sites of synthesis, allowing a separation of biosynthesis from utilization (32). Oral ingestion of creatine depresses its biosynthesis, a response that is reversible when supplementation ceases (32). Despite several decades of research devoted to creatine metabolism, little information, other Paul L. Greenhaff is with the Department of Physiology and Pharmacology, University Medical School, Queens Medical Centre, Nottingharn NG7 2UH. U.K.

2 Creatine / Sf01 than anecdotal reports, has been reported about the influence of dietiuy creatine supplementation upon exercise performance in humans. This seems rather surprising, given the central role that creatine plays in muscle energy metabolism. Role of Creatine in Muscle Energy Metabolism and Fatigue In human skeletal muscle, creatine is ordinarily present at a concentration of about 125 mmol/kg dm. A reversible equilibrium exists between creatine and PCr, and at rest approximately 60% of the creatine content of muscle is in the form of PCr. The availability of PCr is one of the most likely limitations to muscle performance during brief, highpower exercise (19,22), because the depletion of PCr results in an inability to resynthesize adenosine triphosphate (ATP) at the rate required. The availability of free creatine has also been ascribed a central role in the control of PCr resynthesis, with its role in the regulation of mitochondrial ATP production during steady-state contraction being subject to much debate (4, 25, 30, 33). Regardless of this debate, human studies involving maximal contraction (19) and studies on laboratory animals (28), including those involving depletion of muscle creatine stores by feeding the creatine analogue P-guanidinopropionate (24), are in agreement that creatinemr availability is essential to muscle function during short-duration maximal exercise. Several studies in humans have attempted to determine the rates of ATP resynthesis from PCr and glycolysis during 30 s of near maximal isometric contraction (19) (Table 1). They have demonstrated that the rate of PCr utilization begins to decline after only 1.28 s of contraction, while the corresponding rate from glycolysis does not peak until after about 3 s of contraction, suggesting that the rapid initial utilization of PCr buffers the momentary lag in energy provision from glycolysis. Furthermore, there appears to be a progressive decline in rates of ATP provision from both PCr and glycolysis after their initial peak rates. For example, the rates of ATP provision from PCr and glycolysis during the final 10 s of maximal contraction in mixed-fiber human skeletal muscle amount to 2% and 40%, respectively, of their peak rates of ATP production. Interestingly, Table 1 Rates of Anaerobic ATP Production From Phosphocreatine (PCr) and Glycolysis During Maximal Contraction in Human Skeletal Muscle Duration of stimulation (s) PCr ATP production (mrnol. s-i. kg-' dm) Glycolysis Note. Rates were calculated from metabolite changes measured in muscle biopsy samples obtained during intense, intermittent, electrically evoked isometric contraction.

3 S102 / Greenhaff in parallel with the decline in anaerobic ATP production is a decline in force production and power output. It is tempting to postulate, therefore, that the onset of fatigue is attributable to the decline in ATP provision. Effect of Creatine Ingestion on Muscle Creatine Concentration Muscle creatine is replenished at a rate of approximately 2 g/day, following its irreversible degradation to creatinine. However, creatine ingestion will add to the whole-body creatine pool. For example, 1 kg of raw steak contains approximately 4 g of creatine, but some degradation of creatine does occur during cooking. During periods of dietary creatine supplementation, retention of creatine in muscle tissue is greatest during the initial stages of supplementation; as the creatine dose is increased, less is retained. These findings were mainly derived from studies that measured the urinary concentration of creatine and creatinine following creatine ingestion (3, 7, 9). Not until recently have research findings specific to the analysis of human skeletal muscle been published. It is now clear that the ingestion of 20 g/day of creatine (four doses of 5 g) for 5 days can produce, on average, more than a 20% increase in muscle creatine, of which approximately 20% is in the form of PCr (14, 17). Furthermore, if submaximal exercise is performed during the period of supplementation, muscle uptake of creatine increases even more (17). The majority of tissue creatine uptake seems to occur during the initial days of supplementation; the creatine not retained by the tissue is excreted by the kidneys. It is important, however, to point out that human muscle appears to have an upper limit of creatine storage of mmol/kg dm, which, once achieved, with or without supplementation, cannot be exceeded. Thus, feeding creatine to someone with an already high muscle creatine content or ingesting high doses of creatine for a prolonged period will be of little additional benefit. Second, individuals with the lowest levels of creatine in their muscles appear to achieve the most pronounced increases following creatine ingestion (14, 17) (Figure 1). The normal creatine content of muscle is 125 mmolkg dm, and individuals whose muscles contain less than 120 mmolkg dm can expect to have a >25% increase after dietary creatine supplementation. What determines whether people have high or low contents of creatine in their muscles is not yet clear and needs to be investigated. Interestingly, females, for reasons as yet unknown, appear to have a slightly higher creatine content than do males (12). Furthermore, vegetarians are likely to have a reduced body creatine pool (10); therefore, vegetarian athletes represent a population that presumably could gain significant benefits from creatine ingestion. Recent unpublished findings from our laboratory clearly show that muscle creatine stores remain elevated when higher dose supplementation (20 glday for 5 days) is followed by lower dose supplementation (2 g/day). These findings agree with the earlier suggestions of Fitch (11) that, once absorbed, creatine is "trapped" within skeletal muscle. It appears that low-dose supplementation (3 g/day) for 30 days is less effective at raising muscle creatine stores, at least during the initid2 weeks of ingestion, compared with a higher dose (20 glday) for 5 days. We are currently investigating the natural time-course of muscle creatine degradation following 5 days of 20-g/day ingestion; earlier studies that investigated the time-course of creatinine excretion following creatine ingestion (3, 9), indicated that the decline is likely to be over the course of several weeks, rather than days. Creatine is a low molecular weight compound, and its removal by the kidneys is achieved by diffusion, which is a non-energy-dependent process. Ingestion of 20 g/day

4 Creatine / S103 Pre-Ingestion Post-Ingestion Figure 1 - Individual values for muscle total creatine (TCr) concentration before and after 5 days of Cr ingestion (20 g. day-'). Subjects were numbered 1-8, based on their initial total Cr concentration. for 5 days should therefore be viewed to be of minimal risk to normal, healthy individuals. Ingestion of larger doses will be without question a waste of money. Practical Applications Much media attention has recently been devoted to the use of creatine in sport. As a result, questions have been raised concerning the reported ability of creatine to enhance exercise performance, the appropriate doses of creatine to ingest, the side effects of creatine ingestion, and the ethical issues behind taking this "new drug." Perhaps as a consequence of such widespread press coverage, much misinformation has been generated about creatine and its use. Therefore, it is appropriate to clarify some of the known facts concerning creatine and exercise performance. Other than early contradictory reports on the effects on performance of ingesting the creatine precursor, glycine (8, 23, 27), and anecdotal reports of "Eastern Block" athietes and Bulgarian soldiers supplementing their diets with creatine, little has been published relating to creatine ingestion and exercise performance in humans. In 1981, Sipila et al. (31) reported that in a group of patients receiving 1 g of creatine per day

5 5104 / Greenhaff as a treatment for gyrate atrophy, there was a comment from some of a sensation of strength gain following 1 year of supplementation. Indeed, creatine ingestion was shown to reverse the atrophy of Type I1 muscle fibers associated with this disease; one athlete in the group of patients improved his personal best record for the 100-m sprint by 2 s. More recently, it has been suggested that chronic intravenous administration of PCr can accelerate recovery of muscle mass, strength, and power following the development of disuse atrophy associated with knee surgery (29). In support of these findings are the suggestions that muscle creatine availability is implicated in the control of muscle protein synthesis (5) and that muscle-wasting diseases may be related to abnormalities of creatine metabolism (1 1). In this respect, the influence of chronic creatine ingestion on skeletal muscle mass and composition is of obvious scientific interest but is beyond the scope of this review. Recently published results from placebo-controlled laboratory experiments show that the ingestion of 5 g of creatine four times daily for 5 days can significantly increase the amount of work performed by healthy volunteers during repeated bouts of maximal knee extensor exercise (15). These findings have been confirmed by additional laboratory studies involving repeated bouts of maximal exercise on both friction-braked cycle ergometers (1) and isokinetic cycle ergometers (6) and by controlled "field" experiments in which athletes ran 4 x 300 m and 4 x 1,000 m (18). The consistent finding from these studies is that creatine ingestion can significantly increase exercise performance by sustaining force or work output during exercise. For example, in the study of Greenhaff et al. (15), two groups of subjects (n = 6) performed five bouts of 30 maximal, voluntary, unilateral knee extensions at a constant angular velocity of 18O0/s before and after placebo and creatine ingestion (4 x 5 g of creatine daily for 5 days). There was no difference between muscle torque production during exercise before and after placebo ingestion. However, following creatine ingestion, torque production was increased by 57% in all subjects during the final 10 contractions of the fist exercise bout and throughout the whole of exercise bouts 2, 3, and 4. In the study of Birch et al. (6), two groups of seven healthy male subjects performed three bouts of maximal isokinetic cycling at 80 revolutionslmin before and after creatine or placebo ingestion (4 x 5 g of creatine daily for 5 days). Each exercise bout lasted for 30 s and was followed by 4 min rest. The total amounts of work performed during bouts 1-3 were similar when we compared values obtained before and after placebo ingestion (<2% change). After creatine ingestion, work output for each of the seven subjects was increased during exercise bout 1 (p <.05) and 2 (p <.05), but no difference was observed during exercise bout 3 (Figure 2). It is important to note that, contrary to claims, the effect of low-dose creatine ingestion on exercise performance is unknown. However, our own unpublished results on lower dose feeding (3 glday for 30 days) and tissue creatine uptake suggest that lower dose feeding will, at least in the short term, be less effective than the 5-day, 20- gtday regimen. Recent reports from our group (13) and from others (2) suggest that creatine ingestion has no effect on performance or metabolism during submaximal exercise (Figure 3). This requires further investigation. The positive effect of creatine ingestion on exercise performance has now been established under a variety of experimental conditions. However, the exact mechanism by which creatine ingestion influences performance is not yet clear. The available data indicate that the mechanism likely involves the stirnulatory effect of creatine supplementation on preexercise PCr availability and PCr resynthesis during recovery from exercise

6 Creatine / S105 Placebo Creatine Figure 2 - The change in work production during 3 x 30 s bouts of maximal isokinetic cycling (80 rpm) in humans following 5 days of placebo (20 g glucose polymer. day-') and creatine (20 g. day-') ingestion. Each bout of exercise was separated by 4 min rest. Values represent mean f SEM. (14, 15). Since PCr availability is generally thought to limit exercise capacity during brief, high-power exercise, both of these effects would increase muscle contractile capability by maintaining ATP turnover during exercise. This suggestion is supported by reports showing that the accumulations of plasma ammonia and hypoxanthine are reduced during maximal exercise following creatine ingestion, despite a higher work output being achieved (1,15). More convincing evidence comes from a recent study undertaken in our laboratory, showing that creatine supplementation reduced the extent of muscle ATP loss during two bouts of maximal exercise while simultaneously increasing work output by about 6% (16). Furthermore, recently published results clearly show that an uptake of creatine by skeletal muscle following creatine ingestion can significantly accelerate PCr resynthesis during recovery from intense muscular contraction in humans (14) (Figure 4). Although it is now clear that creatine supplementation can positively affect the performance of brief, maximal exercise, some individuals will probably benefit more than others from creatine ingestion (14). Our results indicate that 5 days of creatine ingestion at a rate of 20 g/day will markedly increase (25%) the muscle creatine concentration of those individuals whose presupplementation creatine concentrations are not very high (i.e., less than about 120 mmol/kg dm). Importantly, however, only these individuals showed an accelerated rate of PCr resynthesis during recovery from intense muscular contraction (Figure 5). As might be expected, subjects who experienced little or no

7 S106 1 Greenhaff o!,.,.,.,.., %\jop max Recovery (min) Figure 3 - Oxygen consumption (VO,), blood lactate concentration, and respiratory exchange ratio (RER) during treadmill running and recovery before (0) and after (0) 5 days of Cr ingestion (20 g. day-'). Exercise was performed for 6 min at intensities equivalent to 50, 60, 65, 70, 75, 80, and 90% of.maximal oxygen consumption (VOzmax). Values represent mean f SEM. 0Ja b,,,,,,, 1 rctt %LO2 max Recovery (min) a. a.,.,.,, I5 %vo2 ma2 Recovery (min)

8 Creatine l S107 tt Figure 4 - Phosphoereatine (PCr; 0, *) and free creatine (Cr; 0, m) concentrations measured in muscle biopsy samples obtained after 0, 20, 60, and 120 s of recovery from intense contraction before (open symbols) and after (closed symbols) Cr ingestion. Values represent mean f SEM for a group of 5 subjects who showed a 25 f 3% increase in muscle total Cr concentration during 5 days of Cr ingestion * (20 g. day-'). - E u * Recovery (s) uptake of creatine into muscle during creatine supplementation demonstrated no change in PCr resynthesis during recovery following creatine feeding. This was possibly because these individuals had a relatively high prefeeding concentration of creatine in their muscles, but this was certainly not the only reason. It is important to note that the average creatine concentration in human skeletal muscle is 125 mmol/kg dm (mean of 8 1 biopsy samples) and follows a normal distribution ranging from 90 to 160 mmol/kg dm. Therefore, a concentration of 120 mmol/kg dm should not be viewed as appreciably low. Thus, more research must be undertaken to elucidate the principal factors that regulate creatine uptake into human muscle tissue. This is clearly exemplified by our most recent unpublished finding that those individuals who demonstrate the greatest muscle uptake of creatine during creatine supplementation

9 S108 / Greenhaff I Pre-Ingestion Post-Ingestion , I Increase In TCr after Cr lngestlon (mmollkg dm) Figure 5 - (a) Individual values for muscle total creatine (TCr) concentration before and, after 5 days of Cr ingestion (20 g. day-'). Subjects were numbered 1-8, based on their initial total Cr concentration. (b) Individual increases in muscle total Cr for the same group of subjects depicted in (a), plotted against the change in PCr resynthesis during recovery from intense contraction after Cr ingestion. Values on the y-axis were calculated by subtracting PCr resynthesis during 2 min of recovery before Cr ingestion from the corresponding value after Cr ingestion.

10 Creatine / S109 also show the greatest improvement in exercise performance during repeated bouts of maximal isokinetic cycling exercise. In conclusion, research concerned with the effects of creatine ingestion on muscle function and metabolism during exercise in healthy normal individuals and in disease states is in its infancy but is sure to progress rapidly. Recent findings indicate that it is important to optimize tissue creatine uptake in order to maximize performance benefits. Creatine should not be viewed as another gimmick supplement; its ingestion is a means of providing immediate, significant performance improvements to athletes involved in explosive sports. In the long run, creatine may also allow athletes to train without fatigue at an intensity higher than that to which they are accustomed. For these reasons alone, creatine supplementation could be viewed as a significant development in sport nutrition. References 1. Balsom, P.D., B. Ekblom, K. Soderlund, B. Sjodin, and E. Hultman. Creatine supplementation and dynamic high-intensity intermittent exercise. Scand. J. Med. Sci. Sports 3~ , Balsom, P.D., S.D.R. Hanidge, K. Soderlund, B. Sjodin, and B. Ekblom. Creatine supplementation per se does not enhance endurance exercise performance. Acta Physiol. Scand , Benedict, S.R., and E. Osterberg. The metabolism of creatine. J. Biol. Chem. 56: , Bessman, S.P., and A. Fonyo. The possible role of mitochondrial bound creatine kinase in regulation of mitochondria1 respiration. Biochem. Biophys. Res. Comm. 22: , Bessman, S.P., and F. Savabi. The role of the phosphocreatine energy shuttle in exercise and muscle hypertrophy. In Biochemistry of Exercise VII, A.W. Taylor, P.D. Gollnick, H.J. Green, C.D. Ianuzzo, E.G. Noble, G. Metivier, and J.R. Sutton, (Eds.). Champaign, IL: Human Kinetics, 1990, pp Birch, R., D. Noble, and P.L. Greenhaff. The influence of dietary creatine supplementation on performance during repeated bouts of maximal isokinetic cycling in man. Eur. J. Appl. Physiol. in press. 7. Bloch, K., and R. Schoenheimer. The metabolic relation of creatine and creatinine studied with isotopic nitrogen. J. Biol. Chem. 131: , Chaikelis, A.S. The effect of glycocoll (glycine) ingestion upon the growth, strength and creatinine-creatine excretion in man. Am. J. Physiol , Chanutin, A. The fate of creatine when administered to man. J. Biol. Chem. 67:29-37, Delanghe, J., J-P. De Slypere, M. Debuyzere, J. Robbrecht, R. Wieme, and A. Vermeulen. Normal reference values for creatine, creatinine and camitine are lower in vegetarians. Clin. Chem. 35: , I I. Fitch, C.D. Significance of abnormalities of creatine metabolism, In Parhogenesis of Human Muscular Dystrophies, L.P. Rowland (Ed.). Amsterdam: Excerpta Medica, 1977, pp Forsberg, A.M., E. Nilsson, J. Wememan, J. Bergstrom, and E. Hultman. Muscle composition in relation to age and sex. Clin. Sci. 81: , Green, A.L., P.L. GreenhaR, LA. Macdonald, D. Bell, D. Holliman, and M.A. Stroud. The influence of oral creatine supplementation on metabolism during sub-maximal incremental treadmill exercise. Proc. Nutr. Soc. 53:84A, Greenhaff, P.L., K. Bodin, K. Soderlund, ande. Hultman. The effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am..I. Physiol. 266:E725-E730, Greenhaff, P.L., A. Casey, A.H. Short, R.C. Harris, K. Soderlund, and E. Hultman. Influence of oral creatine supplementation on muscle torque during repeated bouts of maximal voluntary exercise in man. Clin. Sci , Greenhaff, P.L., D. Constantin-Teodosiu, A. Casey, and E. Hultman. The effect of oral creatine supplementation on skeletal muscle ATP degradation during repeated bouts of maximal voluntary exercise in man. J. Physiol. 476:84, 1994.

11 St 1 0 / Greenhaff 17. Hanis, R.C., K. Soderlund, and E. Hultrnan. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin. Sci. 83: , Hanis, R.C., M. Vim, P.L. Greenhaff, and E. Hultman. The effect of oral creatine supplementation on running performance during maximal short term exercise in man. J. Physiol. 467:74, Hultman, E., P.L. Greenhaff, J-M. Ren, and K. Soderlund. Energy metabolism and fatigue during intense muscle contraction. Biochem. Soc. Trans. 19: , Hunter, A. Monographs of Biochemistry: Creatine and Creatinine. London: Longmans, Green and Co. Ltd., Hunter, A. The physiology of creatine and creatinine. Physiol. Rev. 2: , Katz, A., K. Sahlin, and J. Henriksson. Muscle ATP turnover rate during isometric contractions in humans. J. Appl. Physiol. 60: , Maison, G.L. Failure of gelatin or amino-acetic acid to increase the work ability. J.A.M.A. 115~ , Meyer, R.A., T.R. Brown, B.L. Kri1owicz, and M.J. Kushmerick. Phosphagen and intracellular ph changes durlng contraction of creatine-depleted rat muscle. Am. J. Physiol. 250:C264-C274, Meyer, R.A., H.L. Sweeney, and M.J. Kushmetick. A simple analysis of the "phosphocreatine shuttle." Am. J. Physiol. 246:C365-C377, Needham, D.M. Machina Carnis. The Biochemistry of Muscular Contraction in Its Historical Development. Cambridge, UK: Cambridge University Press, Ray, G.B., J.R. Johnson, and M.M. Taylor. Effect of gelatin on muscular fatigue. Proc. Soc. Exper. Biol. Med. 40: , Sahlin, K., L. Edstrom, and H. Sjoholm. Force relaxation and energy metabolism of rat soleus muscle during anaerobic contraction. Acta Physiol. Scand. 129:l-7, Satolli, F., and G. Marchesi. Creatine phosphate in the rehabilitation of patients with muscle hyponotrophy of the lower extremity. Curr. Ther. Res. 46:67-73, Shoubridge, E.A., and G.K. Radda. A 31P-nuclear magnetic resonance study of skeletal muscle metabolism in rats depleted of creatine with the analogue P-guanidinoproprionic acid. Biochem. Biophys. Acta 805:79-88, Sipila, I., J. Rapola, 0. Simell, and A. Vannas. Supplementary creatine as a treatment for gyrate atrophy of the choroid and retina. New Engl. J. Med , Walker, J.B. Creatine: Biosynthesis, regulation and function. Adv. Enzymol. Relat. Areas Mol. Med. 50: , Walliman, T., M. Wyss, D. Brdiczka, K. Nicolay, and H.M. Eppenberger. Intracellular compaamentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: The "phosphocreatine circuit" for cellular energy homeostasis. Biochem. J. 281:21-40, 1992.