American Fitness Professionals & Associates

By Richard B. Kreider, Ph.D. Exercise & Sport Nutrition Laboratory Department of Human Movement Sciences and Education The University of Memphis

Submitted to the Journal of Exercise Physiology December 5, 1997

Abstract

Creatine is an amino acid which is synthesized endogenously from glycine, arginine and methionine or obtained in small quantities from the diet primarily from meat and fish. Creatine is primarily stored in the muscle as free creatine and phosphocreatine. Short term creatine supplementation (15-25 g/d for 5 to 7-d) has been reported to increase phosphocreatine stores by 20-40%, delay fatigue during explosive sprint performance, and facilitate adenosine triphosphate resynthesis following sprint exercise. Long term creatine supplementation (15-25 g/d for 5 to 7-d and 2 to 25 g/d thereafter for 7 to 54 d) has been reported enhance repetitive sprint performance and promote greater gains in muscular strength and fat free mass during training. Consequently, creatine has become one of the most popular nutritional supplements marketed to athletes in recent times. While not all studies report ergogenic benefits, most studies indicate that creatine is an effective and safe nutritional supplement. However, concerns have been recently expressed in the popular literature regarding unknown long-term side effects and anecdotal reports of greater incidence of muscle cramping/injury. This paper will provide a comprehensive overview of the literature regarding creatine supplementation as well as examine the validity of recent concerns raised regarding creatine supplementation. Key Words: Sports Nutrition, Ergogenic Aids, Exercise

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Introduction

During brief explosive-type exercises, the energy supplied to rephosphorylate adenosine diphosphate (ADP) to adenosine triphosphate (ATP) is determined largely by the amount of phosphocreatine (PC) stored in the muscle (1,2). As PC stores become depleted, performance is likely to rapidly deteriorate, due to the inability to resynthesize ATP at the rate required (1,2). Since the availability of PC stores in the muscle may significantly influence the amount of energy generated during brief periods of high intensity exercise, it has been hypothesized that increasing muscle creatine (Cr) content via creatine supplementation may increase the availability of PC and allow for an accelerated rate of resynthesis of ATP during and following high intensity, short duration exercises (3-6). Initial studies indicate that creatine supplementation may increase muscle creatine content, improve anaerobic sprint exercise, and promote greater gains in strength and fat-free mass during training. Consequently, creatine has become one of the most popular nutritional supplements among athletes in recent times (7). The total Cr pool in the body (free and phosphorylated form) is about 120 g for a 70 kg person (3). Training does not appear to affect total Cr content disproportionate to gains in fat-free mass. Approximately 95% of the total Cr pool is stored in skeletal muscle primarily as PC ( 66%).

The remaining total Cr pool is found in heart, brain, and testes. The daily turnover rate of creatine is approximately 1.6% (2 g for a 70 kg person). About half of the daily needs of creatine are obtained from exogenous dietary intake primarily from meat, fish, and animal products. Endogenous synthesis of creatine from the amino acids glycine, arginine and methionine contribute to the remaining daily needs of creatine (refer to Figure 1). Creatine loading involves increasing dietary availability of creatine in an attempt to saturate muscle concentrations of total Cr and PC. This typically involves a loading period (15-25 g/d for 5-7 days) followed by a maintenance period (2-5 g/d) to maintain saturated stores. However, some studies have maintained loading phase doses up to 12 weeks in and attempt to promote lean tissue accretion during training.

The following paper overviews the available literature regarding the effects of creatine supplementation on muscle creatine content, performance, and body composition. In addition, side effects and concerns which have recently been raised regarding the safety and ethics of creatine supplementation are discussed. The paper concludes with a summary of findings and suggested areas for additional research.

Muscle Creatine Content and Phosphocreatine Resynthesis

Supplementing the diet with 20 g/d of creatine monohydrate for 2 to 7-d has been shown to elevate total creatine content in muscle by 10-25% with 20-40% of the increased intramuscular creatine in the form of PC (4,5,8-19). Initially, there was some evidence that individuals with high initial levels of intramuscular creatine did not appear to benefit from creatine supplementation. However, additional studies revealed ingestion of glucose with creatine increases insulin and promotes greater increases in muscle creatine uptake as well as glycogen synthesis (10,11). Under these conditions, intramuscular creatine content is increased regardless of initial creatine levels.

Since creatine supplementation increases intramuscular PC, a number of studies have evaluated the effects of creatine supplementation on ATP and PC resynthesis following repeated bouts of high-intensity exercise (4,8, 9,12,15,18,19). These studies indicate that creatine supplementation does not appear to alter pre-exercise ATP concentrations. However, the elevated PC concentrations serve to maintain ATP concentrations to a greater degree during a single maximal effort sprint lasting 4 o 10-s. In addition, creatine supplementation enhances the rate of ATP and PC resynthesis following an intense sprint. Consequently, the amount of work performed during a series of successive sprints can be increased. Theoretically, creatine supplementation should improve performance in single effort and/or repetitive sprints involving the phosphagen energy system.

Performance Effects

A number of studies have evaluated the ergogenic value of creatine supplementation in various exercise tasks. In these studies, short-term (5 to 7-d) and/or long-term (7 to 54-d) creatine supplementation (20 to 25 g/d for 5 to 7-d and 2 to 25 g/d thereafter ) was reported to:

1.) increase one repetition maximum performance and/or peak power (17,20-25);

2.) improve vertical jump performance (24,26,27);

3.) increase work performed during sets of maximal effort muscle contractions      (14,15,17,22,23,25,28-31);

4.) enhance single effort sprint performance in sprints lasting 6 to 30-s (19,21,22,23,24,28,32-34);

5.) improve repetitive sprint performance in sprints lasting 6 to 30-s typically with 30-s to 5-min      recovery between sprints (8,21,22,28,32,35-40);

6.) improve high intensity exercise performance in events lasting 90 to 300-s (38,41-43);

7.) increase ventillatory anaerobic threshold (44);

8.) increase maximal exercise capacity (45). The improvement in exercise capacity has been      attributed to increased intramuscular creatine and phosphocreatine content      (4,8,9,12,14,15,16,19,46), greater resynthesis of phosphocreatine (4,8,9,19,40) and/or      metabolic efficiency (8,19,21,23,44,47), and improved quality of training promoting greater      training adaptations(22,24,28,37,39,40).

However, other studies have reported that short-term(20 g/d for 3 to 6-d) or long-term (2 to 3 g/d for 2 to 6 wks) creatine supplementation did not significantly improve:

1. one repetition maximum performance (29)

2. vertical jump performance (26)

3. work performed during low intensity muscle contractions (48)

4. single effort sprint performance in sprints lasting 6- to 30-s (26,36,42,49)

5. repetitive sprint performance in sprints lasting 6 to 60-s with rest recovery of 5- to 25-min

6. between sprints (50-54)

7. high intensity exercise lasting 150- to 600-s (9,35,41,55)

8. low to moderate intensity endurance exercise capacity (46,47,56,57)

9. maximal aerobic capacity (44); or, when creatine is ingested with caffeine (17).

In analysis of these studies, creatine supplementation appears to less ergogenic when supplementation regimens are less than 20 g/d for 5-d (16,49,54) or involve low-dose supplementation regimens (2 to 3 g/d) without an initial high-dose loading period (26,48); in crossover experimental design studies with less than 5-wks washout period between trials (9,16,49); in studies (9,14,48,51,55,57) with relatively small n-size (i.e.,

Moreover, studies which have evaluated prolonged (>7-d), high dose (15-25 g/d for 7 to 54-d) creatine supplementation regimens or provided maintenance doses (3 to 10 g/d) of creatine following a high dose loading phase (20-25 g/d for 5 to 7-d) have all reported ergogenic benefit on strength and/or sprint performance suggesting an enhanced quality of training (20,28,22,24,31,39,40,58,59). Consequently, it appears that creatine supplementation may be more or less ergogenic depending on the amount and length of supplementation, the type of exercise evaluated, and the specific work to rest ratios observed.

Body Composition

Although some studies (29,56,57,60) indicate that short-term creatine supplementation (20 to 25 g/d for 5 to 7-d) does not significantly affect changes in total body mass, most studies indicate that creatine supplementation increases total body mass by approximately a 0.7 to 1.6 kg (12,15,17,34,35). The increased body weight has been theorized to be due to a creatine stimulated water retention and/or protein synthesis (3,15,34,61,62).

Consequently, the effects of creatine supplementation on fluid retention, protein synthesis and body composition has recently become an area of interest. For example, Ziegenfuss et al. (34) reported that 5-d of creatine supplementation increased protein synthesis, body mass, thigh muscle volume, anaerobic capacity and increased intra- and extracellular fluid volume by 2-3%. Moreover, a number of long-term (7 to 84-d) creatine supplementation trials (20 to 25 g/d for 5 to 7-d and 2 to 25 g/d thereafter with or without carbohydrate and/or protein) have reported significantly greater gains in total body mass (20,22,31,58,63-65) and fat-free mass (20,22,24,31,39,58, 59,63-65) with no change in total body water expressed as a percentage of total body weight (31,34,55,58,59,64,65). Consequently, gains in intra- and extracellular fluid appear to be in proportion to gains in fat free mass.

Gains in total body mass and fat-free mass following creatine supplementation are typically 0.8 to 3 kg greater than matched-paired controls depending on the length and amount of supplementation. These gains are typically associated with enhanced sprinting capacity and/or gains in strength. Further, studies indicate that only approximately 30-50 g of creatine is retained in the muscle following 3 to 5-d of creatine supplementation (5,10,11,13,17,36,40). Consequently, it is unlikely that fluid retention can account for all of the gains in fat free mass observed. At present, most creatine researchers feel that creatine may stimulate an initial gain in intracellular fluid serving to increase cellular osmotic pressure and stimulate protein synthesis. The gains in fat free mass and strength observed are most likely due to enhanced protein synthesis and/or the ability of the athlete to maintain a greater training volume. Although additional research is necessary, these findings suggest that long-term creatine supplementation may enhance lean tissue accretion.

Side Effects and Concerns

The only side effect reported from clinical studies investigating dosages of 1.5 to 25 g/d for 3 to 365 days in preoperative and post-operative patients, untrained subjects, and elite athletes has been weight gain (3). Available clinical studies indicate that creatine supplementation may result in:

1.) weight gain and/or maintenance of lean body mass in patients (66,67) and untrained and trained      subjects (20,22,24,31,39,58,59,63- 65);

2.) a slight increase in serum creatine (1.2 to 1.4 mol/l) which is well within normal limits for athletes      (31);

3.) moderate increases in creatine kinase and lactate dehydrogenase (31,68) within normal limits for      athletes apparently due to ability to maintain greater training volume (31);

4.) decreased urea nitrogen/creatinine ratio suggesting less catabolism (31);

5.) positive lipid modifying effects including decreased triglycerides and cholesterol with an      increased HDL cholesterol in athletes and hypertriglyceremic patients(31,69);

6.) improved myocardial metabolism and reduced incidence of ventricular fibrillation in ischemic heart patients (60,70-75). Although additional research is necessary to evaluate the long-term effects of creatine supplementation on medical status, available studies suggest that creatine supplementation is medically safe.

Although no adverse side effects have been reported in the literature from clinical trials, concern has been raised by some physicians, athletic trainers, and dieticians regarding:

1.) a possible suppression of endogenous creatine synthesis;

2.) a possible enhanced renal stress/liver damage;

3.)anecdotal reports of muscle cramping when exercising in the heat;

4.)anecdotal reports of muscle strains/pulls;

5.) unknown long-term effects of creatine supplementation.

While these concerns should be evaluated and addressed, it should be noted that there is no evidence from any well-controlled clinical trials to indicate that these concerns have any validity.

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Endogenous creatine synthesis has been reported to decline during periods of increased dietary creatine intake, however, synthesis returns to normal at cessation of supplementation (3,13). Since creatine is an amino acid, some have raised concern about possible renal stress/liver damage in that high protein diets have been reported to increase renal stress in renal failure patients. However, it is unlikely that adding the equivalent of less than one ounce of protein per day to the diet during the 20 g/d loading period would promote renal stress/failure in healthy subjects. In addition, although creatine levels have been reported to be mildly elevated following creatine supplementation it is likely due to excess creatine being eliminated (5,13,31) and not of pathological etiology. Moreover, no studies have reported elevations in liver enzymes in response to creatine supplementation (31,68). Consequently, there is no evidence that creatine supplementation, when taken at recommended dosages, increases renal stress.

No studies have reported cramping or muscle strains/pulls in relation to creatine supplementation even though many of these studies evaluated highly trained athletes during heavy training periods (24,25,29,31,32,38, 39,40,42,48,50,52,53,55). Proponents of this concern point to the role of creatine in fluid retention which has been perpetuated primarily in fitness magazines, supplement advertisements, and lay articles as well as anecdotal reports from athletic trainers of increased incidence of cramping when exercising in the heat (e.g., during fall 2 a day workouts in American football players). However, as was stated previously, studies evaluating the effect of creatine supplementation on fluid retention have failed to observe an increase in relative total body water. These studies suggest that body water increases in relation to the amount of weight gained. In fact, studies evaluating intra and extracellular fluid shifts show that about half of the water gain is extracellular (15,34). Further, since the etiology of muscle cramping has yet to be determined, it is difficult to attribute cramping to creatine supplementation. Creatine has also been suggested to promote a greater incidence of muscle strains/pulls due to rapid increases in weight and/or strength. Yet, gains in strength and sprint performance are typically 5-8% following creatine supplementation no study has documented an increased rate of injury following creatine supplementation.

Logically, if creatine supplementation promoted cramping and/or greater incidence of muscle strains/pulls, it would not be as popular a supplement among athletes in that they would all be cramping and/or injured and therefore not able to participate in their sport events. Opponents of creatine supplementation have also warned about unknown long-term side effects. While long-term (> one year) well controlled clinical trials have yet to be performed, it should be noted that athletes have been using creatine as a nutritional supplement for over 10 years. Yet, this author is not aware of any significant medical complications that have been directly linked to creatine supplementation.

Conversely, creatine and phosphocreatine are used medically to prevent lean mass wasting post surgically, prevent dangerous arrhythmias, and improve myocardial function in ischemic patients (60,66,71,75). In addition, there is some evidence that creatine supplementation my promote positive lipid modifying effects which may reduce risk to atherosclerosis (31,68). Consequently, from the literature currently available, creatine supplementation appears to be a medically safe practice. Concerns have also been raised regarding the ethics of athletes taking a nutritional supplement which has been reported to enhance performance. Yet, creatine supplementation is similar in practice to carbohydrate loading (i.e, ingesting 200 to 500 g of extra carbohydrate in order to saturate muscle glycogen levels).

Although studies indicate that carbohydrate loading is an effective nutritional strategy to enhance exercise capacity, carbohydrate loading is a well accepted practice. Some are also concerned that athletes may mega dose creatine (i.e., take 50 - 100 g/d) or that creatine supplementation may cause a carryover effect resulting in athletes taking other ineffective and/or potentially dangerous nutritional supplements. However, others feel that proper education among athletes, coaches, and trainers regarding the effects of nutritional supplementation on exercise performance reduces and/or eliminates this risk. Some legal issues have also been raised regarding team supplement administration policies and liability of teams, universities, and athletic governing bodies who provide creatine to their athletes.

Most authorities feel that if teams provide creatine to their athletes, athletes should ingest the supplements on a voluntary basis after being well-educated regarding the known effects. Moreover, it is probably wise to have a formal administration policy to ensure that athletes are not administered excessive amounts of creatine. Finally, some argue that creatine supplements are expensive. While this was true initially, creatine supplements are now being sold for as little as $28 - $50 U.S. dollars per kg (about $0.56 to $1.00 per day when taking 20 g/d) which is less expensive than many popular sports drinks.

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Summary

Based on available literature, the following conclusions can be made.

1. Total creatine availability in muscle is an important contributor to high-intensity exercise     performance and recovery.

2. Creatine supplementation (4×5 g/d for 5-7 days) may increase the concentrations of total Cr, free     Cr, and PC in muscle by approximately 10-40%.

3. Ingestion of glucose with creatine increases creatine uptake to a greater degree as well as     enhances glycogen synthesis.

4. Subjects with high initial levels do not appear respond to creatine loading unless they ingest     creatine with glucose promoting significant increases in creatine and glycogen uptake.

5. Short-term creatine supplementation (4×5 g/d for 5-6 days) may enhance anaerobic performance     capacity during repeated bouts of high-intensity exercise by approximately 5 to 8%.

6. Creatine supplementation during training may improve the quality of training leading to greater     gains in strength and sprint performance.

7. Not all studies have reported improved anaerobic capacity possibly due to differences in length     of supplementation, exercise criterion evaluated, and amount of recovery observed during     repeated bouts of exercise.

8. There is some evidence suggesting that caffeine may negate the ergogenic benefit of creatine     supplementation.

9. Short-term creatine supplementation has been reported to increase total body weight by     approximately 1 kg while long-term body composition studies (1 to 12 weeks) of creatine alone,     creatine with glucose, or creatine added

10. to a protein/carbohydrate nutritional supplement have attributed the increased body weight to a       1.4 to 3.3 kg increase in fat free mass.

11. Based on current data, creatine supplementation appears to be a safe and effective nutritional       strategy to enhance exercise performance.

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Additional research should be conducted to:

a. corroborate reported findings using larger populations (male and female) of untrained and trained     subjects performing various performance criterion;

b. evaluate mechanisms and etiology particularly with regards to fluid retention and protein synthesis;

c. determine optimal supplementation regimens to load and maintain muscle total creatine levels;

d. determine the effects of cycling regimens on anaerobic performance and body composition;

e. determine whether adding other nutrients (e.g., glucose, protein, amino acids, RNA, HMB, etc)     would provide greater benefits;

f. evaluate the short and long-term medical safety of creatine supplementation and whether there is    any validity to anecdotal reports of a greater incidence of muscle cramping and/or muscle    strains/pulls; g. evaluate the effectiveness of creatine supplementation in various medical    populations.

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