Creatine and Phosphocreatine: a Review of Their Use in Exercise and Sport Joseph F
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Creatine and Phosphocreatine: A Review of Their Use in Exercise and Sport Joseph F. Clark, PhD, ATC Objective: Creatine and phosphocreatine (PCr) are impor- buffer, protecting the adenosine triphosphate (ATP) concentra- tant compounds in the normal energy metabolism of muscle. tion. Maintaining muscle nucleotides therefore enhances exer- Recently, it has been shown that dietary creatine (5 to 20 g/day) cise performance and recovery. There have been reports that can increase muscle creatine and PCr, with enhancement in PCr protects the cells from ischemic damage and decreases anaerobic exercise performance after two weeks of adminis- the loss of nucleotides by stabilizing cell membranes. Indeed, tration caused by an increase in anaerobic capacity. intravenous PCr (2-4 g/day) has been administered to cyclists, Data Sources: MEDLINE was searched from 1983 to 1996 resulting in a faster recovery time between training sessions. using key word "creatine" along with "humans," "muscle," Conclusions/Recommendations: It is becoming evident "exercise," and "transport." Also, APStracts, the American that oral creatine supplementation may yield certain benefits to Physiology Society search engine for abstracts, was searched enhance the athlete's performance during maximal anaerobic from 1994 to 1996. exercise and interval training. Data Synthesis: Creatine is transported into the muscle cell Key Words: ATP, ADP, muscle, energy metabolism, creatine by a specific transporter, resulting in increased intracellular kinase, anaerobic exercise creatine and PCr. The PCr is capable of acting as an energy R ecently there has been a great deal of interest in the use neously to form a rapid interconversion of PCr and ATP, which of creatine and, to a lesser extent, phosphocreatine maintains an equilibrium in the muscle. This reaction is readily (PCr) in sports medicine and athletic training. Various reversible and may be used to buffer the ATP concentration by published works claim exercise enhancement and specific rephosphorylating ADP from the energy contained within the benefits with the administration of creatine and PCr to ath- PCr molecule. The other significant effect of the reaction is to letes,1-13 but their utility and possible side effects still need to keep the ADP concentration relatively low in the muscle be examined in greater detail. There are, however, various (which, if elevated, will slow cross-bridge cycling).19 As much reports in the literature in which creatine administration is used as 70% of the immediate high-energy stores contained within for therapeutic purposes 14,15 or in which the absence or skeletal muscle are in the form of PCr.20.21 The total creatine depletion of creatine is detrimental.16 This review is an attempt concentration (PCr + creatine) in striated muscle is about 30 to summarize the current knowledge regarding the application ,imoUg muscle, which represents 4 grams of creatine per of creatine and/or PCr with a focus on sports medicine and kilogram of Type I muscle fibers. For this reason, creatine can muscle physiology. be described as an extract of muscle solids. The cellular The creatine/PCr system plays an essential role in the normal concentration of creatine is determined by specific transporters energy metabolism of muscle because it acts as a buffer for the that transport creatine into the cell with sodium (Na+) against adenosine triphosphate (ATP) concentration.17'18 It can also its concentration gradient.222 25 The concentration of PCr is prevent a rise in the adenosine diphosphate (ADP) concentra- determined by the equilibrium constant of the CK reaction.19 tion, which can slow cross-bridge cycling. In muscle, creatine Therefore, the concentration of PCr in muscle is dependent is reversibly phosphorylated by the enzyme creatine kinase upon the ATP and total creatine concentrations. (CK) in the following reaction: CK ATP + creatine <=======> PCr + ADP + HW. (1) CREATINE SYNTHESIS Creatine is synthesized in the liver and kidney and released The H+ produced in this reaction also means that the CK into the blood stream26 to be actively taken up by the muscle reaction is capable of buffering the pH of exercising muscle. cells via specific transport protein(s). The liver plays an Though important, the pH buffering by CK will not be important role in the control of creatine content in the body addressed in this paper. There are two isoenzymes of creatine because it methylates guanidinoacetate to produce creatine15 kinase found in skeletal muscle and both are required for for release into the blood stream. This methylation reaction normal muscle function. There is a cytosolic form of creatine utilizes the amino acid methionine. Guanidinoacetate is pro- kinase and a mitochondrial form, and they function simulta- duced from the amino acids glycine and arginine in the following reaction: Joseph F. Clark is a lecturer at St. Anne's College, Oxford, and is affiliated with the Department of Biochemistry, Biochemical and Clinical glycine + arginine ======> Magnetic Resonance Spectroscopy Unit, South Parks Rd, University of Oxford, Oxford OX1 3QU, England guanidinoacetate + ornithine. (2) Journal of Athletic Training 45 NH2+ O0 11 NH2 -C-N-CH2-C=O CH3 Creatine O' NH2+ 0' e04 Time 11 I Fig 2. A schematic representation of the relative concentration O=P-NH-C-N-CH2-C=O changes that occur in muscle during two bouts of exercise. The PCr concentration at the start of the anaerobic exercise is greater in the muscle with creatine supplementation compared to control. O' CH3 The PCr concentration falls rapidly in both groups as the PCr molecule is used to buffer the ATP concentration. When exercise stops and the muscle is allowed to recover, the rate of PCr Phosphocreatine recovery is faster in the muscles with creatine supplementation Fig 1. The chemical structures of the creatine molecule (top) and its (this is explained in Fig 3). Furthermore, when the anaerobic phosphorylated counterpart phosphocreatine (bottom). exercise is prolonged in the second bout of exercise, the ATP concentration is better maintained with creatine supplementation. The ATP buffering capacity of the muscle is enhanced due to the The ornithine is used in the urea cycle and the guanidinoacetate increased PCr concentration in the muscle. Note: the rates of is methylated to form creatine (Fig 1; creatine molecule). concentration changes during exercise are dependent upon inten- Therefore the synthesis of creatine requires three amino acids: sity of the exercise. For maximal anaerobic exercise, such as a glycine, arginine, and methionine. The net synthesis of creatine sprint, the entire right hand box of this figure would take about 15 seconds. in the body is 1 to 2 g/day. CREATINE SUPPLEMENTATION about 70% of the people studied had an increase in total muscle creatine and exercise enhancement.20 This was attributed to the Harris et al21'27 have shown that feeding creatine at 2 to 5 fact that some of the athletes (30%) had creatine levels near the g/day increases intracellular creatine and PCr in human mus- physiological maximum. Another study showed that increased cle.3 Greenhaff and colleagues have extended these observa- PCr does not change the maximal force of contraction.27 tions using 5 to 20 g/day creatine.9 28'29 They fed volunteers 5 g Increases in maximal force may occur if there is an anabolic of creatine four times a day with a daily total of 20 g. This is action of creatine or PCr, but these observations have not been considered the loading dose and is decreased to 2 to 5 g/day fully evaluated.14'30 (maintenance dose) after 6 to 14 days, which is continued Active uptake of creatine has been found in all muscle cells throughout the period of training. If athletes are given lower studied, including skeletal, heart, and smooth muscles.19'25'3' doses (2-3 g/day), without the loading dose, there is still Creatine has been shown to have an anabolic effect on muscle increased muscle creatine but with a slower rate of accumula- tissues'4'30 because it caused an increase in protein synthesis.30 tion. The current evidence is that the best loading of muscle Elevation of PCr in the muscle cell is also capable of creatine occurs during normal training and occurs concomitant stimulating protein synthesis in the cell organelles. Interest- with a low-fat, high-carbohydrate diet.29 ingly, Bessman and Mohan30 likened the PCr stimulation of In the intestine, creatine is absorbed unchanged from the protein synthesis to that of exercise or insulin-stimulated lumen and passes directly into the blood stream. Following oral growth. Even in humans there was a 46% increase in the size creatine administration serum creatine rises, and the amount of of Type II muscle fibers in gyrate atrophy patients fed 1.5 creatine taken into the cells increases, leading to higher g/day of creatine for one year.'4 Conversely, inhibition of intracellular PCr levels" 2 (See Fig 2). This extra PCr enhances normal creatine metabolism prevents normal muscle growth as anaerobic output and muscle peak torque production28 (as well as decreases protein and lipid synthesis.'6'32 Oral admin- measured using a Cybex II isokinetic dynamometer; Lumex, istration of creatine monohydrate to men and women has been Inc., Ronkonkoma, NY) in the working skeletal muscle. This found to lower plasma total cholesterol (6%), triacylglycerols was seen in athletes fed 24 g/day for 5 days, and the exercise (22%), and very-low-density lipoprotein-C (23%) after 56 days protocol was five sets of quadriceps contractions, with 30 of administration (5 g/day).33 repetitions in each set. Part of the reason for the increase in muscle peak torque production was attributed to the acceler- CREATINE TRANSPORT ated rate of PCr resynthesis. Greenhaff et all' pointed out, however, that the dietary supplementation with creatine did not Creatine is actively taken up into the cell via a specific increase total muscle creatine in all athletes.