Creatine Supplementation.

NH 2 C N CH 2 COO Creatine Supplementation. Introduction The sporting field of today is ultra-competitive. The professionalisation and influx of money to many sports has drawn athletes from across the globe. Using all potential avenues - physical, psychological, nutritional, etc. - for improved performance has become vital to be competitive on the world stage. Nutritional supplements have become popular with athletes. Creatine monohydrate is one such supplement that has become widespread in recent years due to its availability, relatively low cost and legality. Many track athletes - including Linford Christie - have used creatine monohydrate (Cr.H 2 O) for its claimed benefits. This is despite the fact that the benefits of creatine supplementation have yet to be conclusively proven in laboratory tests. Studies involving swimmers 5,18, rowers 15, sprinters 14, rugby league players 10 and cyclists 2,4 have given results both for and against creatine supplementation. The aim of this paper is to critically analyse the current literature, outline the possible benefits / side effects of creatine supplementation and to provide the athlete with recommendations. Creatine Facts & Chemistry Creatine (also called N-amidinosarcosine) was discovered by scientists in 1832 1. In the late 18th century it was established that a portion of ingested creatine was retained in the body 1. Ninety-five percent of the creatine in the body is in the skeletal muscle 9,10,12,13, the remainder found mostly in the heart, brain and testes 1. A small amount of creatine is also found in the blood plasma 13. Creatine is found in two forms in the body, two-thirds as creatine phosphate 9 (PCr or phosphocreatine 20 ). The remaining one-third exists as free creatine 9. Together, free creatine and PCr form the total creatine pool 1. There is 3-4 times the amount of PCr in resting muscle compared to adenosine triphosphate (ATP) 9,13,19. PO 3 NH 2 CH 3 p.1

Fig. 1. Structure of creatine in its free and phosphorylated (PCr) forms 1,21. Creatine use in the body The phosphagen energy system (also called alactic, ATP-PC system) provides the body with energy for short duration, high intensity exercise. Two compounds are predominant in this system - adenosine triphosphate (ATP) and phosphocreatine (PCr). ATP is the energy currency for all cells in the body 3,8,12,16,19,20,21. In resting muscle ATP has a concentration of approximately 24 mmol/kg 9. A fall in this concentration of 25-30% has been noted to cause strong fatigue leading to exhaustion 9,20. PCr functions in the muscle to buffer this drop in ATP concentration 1,8,9,12,13,16,19,20,21. PCr transfers its high energy phosphate unit to adenosine diphosphate (ADP) to resynthesise ATP as follows 8,9,20 : ATP ----> ADP + Pi ADP + CP ----> ATP + C Pi represents inorganic phosphate. Creatine kinase acts as the catalyst for this reaction which takes place in the muscle myofibrils 9,3,12. This reaction allows higher workloads to be sustained for greater periods by providing the ATP necessary for muscle contraction 8,20. While the buffering of ATP is the primary task of PCr, it also functions in other processes. One such process is the phosphocreatine shuttle which transfers energy from the mitochondria to the myofibrils as phosphate units 1,9,3,11. This process acts during recovery from exercise 3,11. During recovery from exercise ATP is regenerated in the mitochondria by oxidative phosphorylation. A high energy phosphate is removed from ATP and attached to free creatine for transport to the muscle myofibril 3,11. PCr is the form of transport for the ATP-donated phosphate 3,11 (see fig. 2). Only 8% of the total creatine pool is able to function as part of the phosphocreatine shuttle 13. myofibril mitochondria ATP Cr Cr ATP CK CK ADP + Pi PCr PCr ADP + Pi CK represents creatine kinase, Cr represents free creatine p.2

Fig. 2. The phosphocreatine shuttle 3,11. PCr also impacts on the glycolytic energy system (also called lactic system) by buffering the build up of lactate 9,15. When lactate (or more correctly hydrogen ions) levels reach a critical point the ph of the cell decreases to an extent where muscle contraction is no longer possible and fatigue occurs 9. This occurs due to the effect of the lower ph on glycolysis enzymes 20. PCr can buffer the build up of hydrogen ions through its breakdown 9. PCr 2 + ADP 3 + H + ----> ATP 4 + Cr PCr accounts for 30% of the total buffering capacity of the muscle 15. The reaction utilises the hydrogen ions produced from the dissociation of lactic acid to replenish ATP and buffer ph decreases. Creatine intake, synthesis and uptake Creatine (like other metabolic intermediates) is consumed by the body to provide energy. The average consumption for a seventy kilogram male is two grams per day 1,9,14. Creatine levels need to be maintained to replenish this source of energy. This is achieved through two means - exogenous intake or internal synthesis 1,13,21. Most people are able to maintain creatine levels in the body by consuming meat or fish (exogenous intake) which are the best nutritional sources of creatine 1,9,12,13. However, the average intake of creatine is only one gram per day 1,9,12,13. The shortfall is compensated for by the bodies ability to synthesise creatine (internal synthesis) from the amino acids glycine, arginine and methionine 1,13,21. This takes place predominantly in the kidneys, with some synthesis occurring in the liver and pancreas 9. With creatine supplementation the exogenous intake is increase by approximately ten times with the aim of increasing the stored amount in muscle 7. However, not all of the excess creatine is used by the body - much of it is passed in the urine 12. Several factors interplay to determine the amount of creatine that is retained within the body. p.3

glycine + arginine transamidinase enzyme guanidinoacetate + ornithine S-adenosylmethionine CREATINE + adenosylhomocysteine Fig. 3. Synthesis of creatine in the body 1. The most noted of these factors is the baseline or presupplementation levels of creatine in the individual 1,12,13. Several reviews have cited that the greatest increases in creatine levels have occurred in subjects with the lowest presupplementation levels 1,9,12,13. Maughan 9 citing increases in subjects of up to 50%! Nuttall 12 and Maughan 9 and have further suggested the existence of an upper level of creatine storage in the body. Oopik 13 has combined these findings in stating that the level of uptake is inversely related to presupplementation levels. Very active people tended towards having a high initial total creatine pool 8, while vegetarians tended towards a low initial total creatine pool 1,9,12,13. McKardle et al. 8 and Conroy et al. 6 cite the training effect of increased phosphocreatine levels, while vegetarians have a lower dietary intake of creatine 9. The site of exercise has also been implicated in the level of creatine uptake - more specifically, which muscles increase their total creatine storage. Oopik 13 p.4

cites a study by Harris, et al. in which creatine uptake was isolated to the limb that was exercised. No increased creatine levels were noted in the opposing limb. Oopik 13 further suggests that the level of creatine uptake is the result of individual differences. A single five gram dosage resulted in vastly different blood plasma concentrations of free creatine (no study recorded). Oopik 13 recommends the individualisation of creatine dosages to allow for these individual differences. Further differences in creatine levels and uptake may arise from muscle fibre composition 9, gender 1,9,15 and age 1. Little information is available on the period of increased creatine levels after supplementation has ceased. However, Maughan cites a personal communication from Greenhauff stating that muscle creatine levels will continue to be elevated for several weeks after a 4-6 day supplementation program 9. Supplementation, WHY? From the information presented the reasons for creatine supplementation become clear - an increased total creatine pool. However, the performance implications of an increased creatine pool are not simple to comprehend. Furthermore, scientific laboratory testing has not been able to conclusively show some aspects of the proposed benefits of creatine supplementation. An increase in the total creatine pool will increase both the concentrations of free creatine and PCr 1,2,4,5,7,9,12,13,14,15,18. This has been shown to aid performance by: ø extending power output 1,2,13 ø enhancing lactate buffering 1,2,4,9,10,13 ø improved PCr resynthesis in recovery 1,2,10 In studies extended power output, enhancing lactate buffering and improved PCr resynthesis has been show through lower rates of fatigue in prolonged or repeated bouts of activity. These benefits have been shown in cycling 1,2,4,13, running 9, rugby league players 10 and maximal voluntary knee extensions 1,13. Some studies have failed to replicate these results. However, this has generally occurred through experimental design problems in the dosage or time period of supplementation, the training level of the subjects and the appropriateness of the time period/distance. p.5

Thompson et al. 18 looked at the metabolism and performance of swimmers at 100 and 400 metre distances. Subjects were given creatine or placebo supplementation for six weeks. However, the dosage was only 2g per day. Considering that the subjects were trained swimmers, and that baseline levels were probably high, this level of supplementation may not have been high enough to elevate plasma creatine and enhance muscle uptake 13. Changes in anaerobic and aerobic metabolism 18 from creatine supplementation is worthy of further investigation. A review by Tarnopolsky 17 refers to a common problem with creatine supplementation studies as seen in the study by Birch et al. 4. All studies citied in this review have utilised pre and post supplementation testing as the means of determining the effectiveness of creatine supplementation. This method doesn t effectively resolve the randomisation of subjects issue. Birch et al. 4 provide an illustration of this. This study claimed to show an increase in total work of supplemented subjects. Indeed, there was a significant increase in supplemented subjects from the pre to the post supplementation tests. However, the raw total work figures for the supplemented group were still below those achieved by the placebo group. This was true for ALL pre and post tests! A crossover design may provide a more comprehensive determination of supplementation benefits. However, the substantial time lag before baseline levels return 9 make this type of study difficult to administer. Rossiter et al. 15, Redondo et al. 14 both failed to show a statistically significant improvement in power maintenance. These results may have occurred due to the rowers being well trained and the distance used being inappropriate to show any improvement respectively. A study examining the effects on sprint performance over a longer distance - perhaps 100-200m - may show the beneficial effects of creatine supplementation. It is important to note in the study by Rossiter et al. 15 an increase in performance was recorded (1%), but this improvement was not statistically significant. At the upper levels of competition a slight improvement may be enough to make considerable performance gains (in terms of a placing, ranking, etc). Such considerations may be important to the elite athlete. Although it is not clear from the information that has been provided, it is also possible that creatine will have an effect on aerobic capacity 13. This occurs indirectly and is due to what are called rate limiting factors. These factors are compounds which the reaction taking place is dependant upon to proceed. p.6

Oopik cites Mahler in proposing that ADP is the rate limiting substance for oxidative phosphorylation 13 ie. ADP is required to accept the high energy phosphate produced by oxidative phosphorylation. In turn, creatine is the rate limiting factor in the mitochondrial creatine kinase reaction 13 ie. the transfer of phosphate from ATP to free creatine (see fig. 2). Creatine availability effectively becomes the rate limiting factor for oxidative capacity 13. ADP creatine RLF RLF ADP + Pi ATP ATP + Cr ADP + PCr oxidative phosphorylation (mitochondria) RLF represents rate limiting factor Fig. 4. Creatine and aerobic capacity 13. phosphocreatine shuttle (mitochondria to myofibril) Oopik has demonstrated the increased aerobic capacity of rats using creatine supplementation in a swim to exhaustion exercise 13, although these result conflict with a separate study cited in Oopik by Ohira et al. This theory also remains unproven in human subjects. In a review by Balsom et al. 1 a study involving human subjects is citied in which endurance (aerobic) performance was significantly impeded by creatine supplementation. This is linked to an increase in body weight of creatine supplemented subjects 1,5. In Maughan s review 9 a study by Green et al. is cited in which submaximal incremental treadmill running was assessed. Exercise performance was not recorded but no effect was found for creatine supplementation on cardiorespiratory function and metabolic parameters. The effects of creatine supplementation on aerobic capacity require further investigation. Supplementation, HOW? Almost all studies involving creatine supplementation have looked at the effects of short term, high dosage programs 2,4,5,10,14,15,18. A typical program has used 4-5 doses a day of 4-5 grams of creatine monohydrate (mixed with glucose or polycose) over 4-6 days 9,12. Using this program has given the greatest increase in muscle total creatine levels 12. p.7

Other programs for creatine supplementation have used 3g per day for 14 days and 30 days 1,12. However, the uptake of creatine on these programs was less than the 20g per day for 5 day approach 1,12. It should be noted that the side effects of remaining on a high dosage program for an extended period are unknown, but is considered safe for a short period. Problems / other considerations with creatine supplementation Detrimental side effects of creatine supplementation have received little attention in current publications. At present the only known side effect is a possible increase in body weight 1,2,13. This has been attributed to changes in the protein synthesis and water retention in skeletal muscles 1,13. Could this be due to the use of creatine monohydrate (Cr.H 2 O) as the supplement? Meir has also noted that some subjects suffered nausea, diarrhoea and muscle tightness as well as an increase in body weight when taking creatine monohydrate 10. Only 23% of subjects suffered nausea or diarrhoea which lasted approximately 24 hours. 83% of the subjects indicated tightness in the muscles particularly in the lower extremities. Increased plasma urea has been shown to occur in rats with creatine supplementation 13. Although this has not been shown in humans, if it does occur this will be an important parameter to monitor in athletes who are taking creatine supplements. The accumulation of urea has been attributed to the switching off of the transamidinase enzyme resulting in excess arginine. This arginine is speculated to be converted into urea which appears in the blood plasma 13. The measurement of blood urea nitrogen (BUN) and plasma creatinine can be conducted to monitor the renal functioning of athletes. BUN measures the nitrogen in blood that is found in urea 19. A high BUN measure is an indication of poor renal function. Creatinine is a product of catabolism of PCr in muscle cells 18,19. Plasma creatinine measures the amount of creatinine in the blood and is normally at a steady level 19. Again, high levels indicate poor renal function. These measures could be valuable to athletes giving early warning if side effects do occur from long term creatine supplementation. Maughan raises the notion of diseases associated with high meat intake possibly being stimulated by creatine supplementation, in particular cancer of the colon 9. Oopik 13 and Balsom et al. 1 postulate on a similar effect on the renal system 13. Does excessive exogenous intake and the subsequent switching off of the internal synthesis of creatine have any effect on kidney function? Will the p.8

synthesis mechanism be impaired when the exogenous intake is removed 1? These questions require further study before definitive answers can be given. Low levels of creatine have been implicated in diseases such as gyrate atrophy, rheumatoid arthritis and fibromyalgia 1,7. Gyrate atrophy has been studied and found to be treatable through creatine supplementation of 1.5g per day 1. The atrophy also reappeared after supplementation 1. The treatment of other muscle disorders associated with low creatine levels may be possible. With any performance enhancing substance there is the question of the ethical and moral issues relating to its use. While these issues need to be dealt with by the coach and athlete, Maughan raises an interesting comparison between caffeine and creatine 9. Maughan asks if caffeine is restricted in the amount legally allowed why is no such restriction imposed on creatine? To my knowledge there is no test that will distinguish between creatine ingested in food and that consumed in excess. Indeed, the usual method of supplementation is to dissolve the creatine powder in tea, coffee or fruit juice. Recommendations for the athlete Based on the current literature is appears that creatine supplementation can enhance performance during high intensity intermittent exercise. This may be of particular relevance to team sport athletes and athletes in training. More broadly, an activity which consists of intermittent, short periods of high intensity work followed by rest. Examples may include the various football codes and court sports such as hockey or tennis. Any effects of supplementation on single effort sprint type activities will depend on the duration of the activity. There may be benefits for maximal activities lasting from a few seconds to a few minutes. More research is needed before a definite guideline can be given. The training considerations deserve more description. Nuttall 12 has suggested that supplementation may allow increased training loads to be achieved due to facilitated recovery. A greater training effect may be able to be achieved. Although creatine supplementation has resulted in increased free creatine and PCr concentrations for many subjects this may not occur for all. If an athlete is considering supplementation monitoring of urine for creatinine and creatine may be useful for determining uptake and possible renal damage. Furthermore, the dietary habits of the athlete may be of importance when considering the dosage to be given. Due to the time lag for increased creatine levels and the unconfirmed safety of long term creatine supplementation it is recommended that athletes p.9

cycle supplementation in monthly blocks. One week with supplementation to three weeks without should be adequate to maintain creatine stores. Once again, individual differences will apply. Athletes who are vegetarians may be able to make large gains from creatine supplementation due to low baseline levels. Again monitoring, dosage, and the type of activity performed become important. While the hypothesis for enhanced endurance performance exists, it is yet to be clinically proven. Indeed some studies have showed detrimental effects of supplementation on endurance performance. Supplementation is not recommended for athletes who engage in endurance activities. p.10

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