Effects of Creatine Supplementation on Exercise ... - Semantic Scholar

REVIEW ARTICLE

Sports Med 1999 Jul; 28 (1): 49-60 0112-1642/99/0007-0049/$06.00/0 © Adis International Limited. All rights reserved.

Effects of Creatine Supplementation on Exercise Performance T.W. Demant and E.C. Rhodes School of Human Kinetics, University of British Columbia, Vancouver, British Columbia, Canada

Contents 1. Historical Background . . . . . . . . . . . . . . . . . . . 2. Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . 3. Creatine in Skeletal Muscle . . . . . . . . . . . . . . . . 3.1 Distribution in the Body . . . . . . . . . . . . . . . . 3.2 Creatine Concentration in Different Fibre Types . 3.3 Effects of Age and Sex . . . . . . . . . . . . . . . . 3.4 Effects of Training . . . . . . . . . . . . . . . . . . . 4. Roles of Creatine Phosphate (CP) . . . . . . . . . . . . 4.1 Temporal Energy Buffer . . . . . . . . . . . . . . . 4.2 Spatial Energy Buffer . . . . . . . . . . . . . . . . . 4.3 Proton Buffer . . . . . . . . . . . . . . . . . . . . . . 4.4 Glycolysis Regulation . . . . . . . . . . . . . . . . . 5. Creatine Supplementation . . . . . . . . . . . . . . . . 5.1 Creatine Supplementation and CP Resynthesis . 5.2 Side Effects . . . . . . . . . . . . . . . . . . . . . . 6. Creatine Supplementation and Exercise Performance 6.1 Incremental and Endurance Exercise . . . . . . . 6.2 High Intensity Exercises . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

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While creatine has been known to man since 1835, when a French scientist reported finding this constituent 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 2g 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 20g per day for

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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.

In the world of athletics, much is often claimed yet little is substantiated. In the early 1990s, a new ergogenic aid was being proclaimed as a true performance enhancer. Fuelled largely by rumours involving British sprinters and their gold medal performances, creatine quickly became hailed as a true ergogenic aid for short term, power exercises. Its presence in health stores and on the shelves of fitness club snack shops has propelled it into the spotlight in the athletic and fitness community. Amid claims of increased power and strength, decreased performance time and increased muscle mass, creatine’s claims are recognised by both elite and recreational athletes. However, with all the hype surrounding this ‘new’ wonder supplement, researchers have sought to determine fact from fiction and provide a credible input into this craze. While creatine is being hailed as a new ergogenic aid, its presence in the human diet dates back to our earliest days. As a constituent of meat, creatine has always been part of an athlete’s diet, and yet it is only now that we are hailing its value. 1. Historical Background Creatine was first identified by the French scientist Chevreul in 1835, when he reported finding a new organic constituent of meat. He named this new constituent creatine. Due to detection problems, it was not until 1847 that Liebig was able to confirm the presence of creatine as a regular constituent of meat.[1] Liebig also observed that the  Adis International Limited. All rights reserved.

meat of wild foxes killed in the chase contained 10 times the amount of creatine as that of foxes in captivity. He thus concluded that work results in the accumulation of creatine. At this time, the researchers Heintz and Pettenkofer discovered a substance in urine, later identified by Liebig as creatinine, a byproduct of creatine degradation. The concentration of creatinine in urine was directly related to muscle mass, which suggested its link to creatine.[2] By the beginning of the 20th century, research into creatine ingestion was already taking place. Studies reported that not all the ingested creatine was reclaimed in the urine, indicating that the body retained some. In 1912 and 1914, Denis and Folin reported that the Cr of cat muscle increased by 70% following creatine ingestion. By 1923, Hahn and Meyer had estimated the total creatine content of a 70kg man to be approximately 140g, an amount close to that proposed.[2] Soon after, Schlossmann and Tiegs reported that ‘diffusible’ creatine increased during muscle contraction.[1] In 1927 and 1929, Fiske and Subbarow discovered a labile phosphorus in the resting muscle of cat, which they named phosphocreatine or creatine phosphate (CP). They showed that during electrical stimulation of skeletal muscle, CP concentrations decreased for a period of time, but then increased to previous levels following a recovery period.[2] These studies have led to the identification of free creatine (Crfree) and CP, Sports Med 1999 Jul; 28 (1)

Creatine Supplementation and Exercise Performance

and their role as key intermediates of skeletal muscle metabolism.[3] Through the re-introduction of the needle biopsy technique and the invention and use of nuclear magnetic resonance (NMR) spectroscopy techniques, researchers have been able to study the breakdown and resynthesis of adenosine triphosphate (ATP) and CP in skeletal muscle metabolism,[4] as well as determine the role CP plays in skeletal muscle metabolism. While studies involving creatine supplementation can be traced back to before the 20th century, it appears that its influence on humans has only recently been investigated.[3] Therefore, while creatine and its involvement in muscle metabolism is not a new discovery, its potential for aiding performance via supplementation or ‘loading’ is one of the latest focuses in ergogenic research. 2. Biochemistry The synthesis of creatine involves the 3 amino acids glycine, arginine and methionine. The synthesis process begins with the transfer of the amidine group from arginine to glycine, a process of transamidination which forms guanidinoacetate and ornithine, a reversible reaction catalysed by the enzyme glycine-amidine-transamidinase. Creatine is formed by the addition of a methyl group from (S)-adenosylmethionime, which requires the enzyme methyltransferase for the irreversible reaction known as transmethylation.[5] The enzymes involved in the synthesis of creatine are located in the kidney, liver and pancreas. Creatine is produced outside the muscles and thus must be transported to skeletal muscle via the blood stream. Normal plasma concentrations of creatine range from 50 to 100 µmol/L.[6] Once it arrives at the skeletal muscle, uptake of creatine occurs against a concentration gradient. Creatine enters a number of cell types via an Na+ dependent neurotransmitter transporter family related to the taurine transporter and members of the subfamily of γ-aminobutyric acid/betaine transporters.[7] The presence of insulin[8] and triiodothyronir (T3)[9] ap Adis International Limited. All rights reserved.

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pears to enhance the uptake of creatine, but is decreased when vitamin E is deficient.[10] 3. Creatine in Skeletal Muscle 3.1 Distribution in the Body

Approximately 95% of the body’s total creatine is found in skeletal muscle, with the remaining 5% being mostly found in the heart, brain and testes. In skeletal muscle, 40% of the creatine is Crfree, while the remaining 60% is in the phosphorylated form, CP.[11] In 1974, Harris et al.[12] measured freeze dried muscle (dm) biopsy samples taken from the quadriceps femoris of 81 untrained male and female volunteers, aged 18 to 30, and reported a mean total Cr of 124.4 mmol/kg, of which 49.0 mmol/kg was Crfree and 75.5 mmol/kg was CP. This value of total Cr has since been regarded as the standard reference of Cr in skeletal muscle. In the absence of exogenous creatine, the rate of creatine and CP being degraded to creatinine via a non-enzymatic, irreversible reaction is estimated at approximately 1.6% per day.[13] The creatinine is filtered in the kidneys by diffusion, from which it is excreted in the urine.[14] Therefore, a 70kg person with a total creatine pool of approximately 120g has a turnover rate of approximately 2g per day. This lost creatine is replaced by both endogenous and exogenous sources. It is believed that endogenous synthesis is to some degree regulated by exogenous intake, likely through a feedback mechanism.[15] Since creatine is predominately found in meat, fish and other animal products, with only traces found in some plants, vegetarians and others on a creatine-free diet rely exclusively on endogenous synthesis to meet their daily needs. This exclusive reliance on endogenous synthesis results in a reduced total Cr in those with creatine-free diets.[16] From a mixed diet the average intake of creatine is estimated at 1g per day, with the remaining 1g being endogenously synthesised. Sports Med 1999 Jul; 28 (1)

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3.2 Creatine Concentration in Different Fibre Types

Tesch et al.[17] reported that the CP content at rest in type II (fast twitch) and type I (slow twitch) fibres was 82.7 ± 11.2 and 73.1 ± 9.5 mmol/kg dry weight, respectively. This represented a significant difference in CP content between fibre types. These findings support the findings of Essén[18] and Edström et al.,[19] who also reported higher resting CP levels in fast twitch than in slow twitch fibres or in vastus lateralis compared with soleus muscle in humans. Tesch et al.[17] also reported that following 30 seconds of maximal exercise, CP content in fast twitch fibres was lower than in slow twitch fibres, but after 60 seconds of recovery slow twitch fibres had significantly higher CP concentrations, suggesting that slow twitch fibres have a greater capacity to resynthesise CP during recovery. These results appear consistent with the idea that CP resynthesis is a oxygen dependent process. Slow twitch fibres are better suited for restoration, due to greater capillary density, greater mitochondrial content, higher activities of oxidative enzymes and greater respiratory capacity.[20] 3.3 Effects of Age and Sex

Based on studies by Möller and co-workers,[21] there appears to be no difference between elderly and young individuals with regards to total creatine content. However, the level of Crfree was found to be higher, and CP content lower, in elderly volunteers. Comparisons of levels of Crfree and CP in skeletal muscle in males and females appear equivocal, with 1 study[22] reporting that females have a higher total creatine level relative to tissue weight, while another reported no significant difference between males and females.[3] To date, there is not enough evidence to suggest a difference does or does not exist between males and females with regard to total creatine content, and more research is required.  Adis International Limited. All rights reserved.

3.4 Effects of Training

While early thought suggested an increased CP level in trained versus untrained individuals, more recent studies using NMR spectroscopy failed to show any significant differences.[23] A study by Bernus et al.[24] reported higher levels of CP in the quadriceps muscles of sprinters compared to marathon runners. However, the authors suggested that the sprinters would have a higher percentage of fast twitch fibres, and thus the difference was due to fibre type and not training effects. In general, there is little conclusive evidence to suggest any definite changes in skeletal muscle Cr due to high intensity, resistance or endurance training, or differences between trained and untrained individuals. 4. Roles of Creatine Phosphate (CP) 4.1 Temporal Energy Buffer

Physical activity of short duration and high intensity, such as a 100m dash, 25m swim or weight training, requires an immediate source of energy. The energy required for these types of activities is almost exclusively provided by high energy phosphate, ATP and CP, which are stored within the muscles required during activity.[20] While the energy for muscle contraction is directly supplied by the breaking of the high-energy phosphate bond in the ATP molecule, forming ADP + Pi, the breakdown of CP supplies the energy required for quick resynthesis of ATP from ADP. This reversible reaction is catalysed and controlled by the creatine kinase enzyme (CPK). CP + ADP ← CPK → ATP + Cr

The reaction proceeds to the right following the breakdown of ATP to ADP, when there is a demand for energy by the muscle, and is driven to the left by the removal of ADP at energy generating sites such as the mitochondria. 4.2 Spatial Energy Buffer

Years of investigation into the role of phosphogens has led researchers to suggest that creatine and Sports Med 1999 Jul; 28 (1)


CP diffuse between mitochondrial production sites and muscle utilisation sites. Bessman formally proposed this diffusion process in 1972, referring to it as the ‘phosphorylcreatine shuttle’.[25] This CP energy shuttle involves 3 areas: (i) a peripheral terminus located at the utilisation site, which in the case of muscle is the myosin heads; (ii) an energy generating terminus which is located at the mitochondria; and (iii) a transversible space between the areas of production and utilisation.[26] When the CP molecule is broken down via an isoenzyme of CPK, providing energy for ATP resynthesis, the resulting Crfree diffuses toward the mitochondrial membrane. At the membrane, the creatine is phosphorylated via another isoenzyme of CPK, using the energy from the breakdown of ATP to ADP, via adenosine triphosphatase, in the mitochondrial membrane. This resynthesised CP then diffuses back to the myosin heads where its potential energy is once again utilised in ATP resynthesis.[25] 4.3 Proton Buffer

At the onset of maximal physical activity, blood lactate accumulation begins to occur. The accumulation of lactate results in an increase in H+, which in turn results in a decrease in muscle pH, leading to decreased muscle performance. H+ is also increased by the hydrolysis of ATP. Creatine acts to buffer pH by utilising H+ when the CPK reaction favours ATP resynthesis. In preventing H+ build up creatine helps prevent acidification of the muscle cells and maintain a normal pH.[20] 4.4 Glycolysis Regulation

The onset of lactate accumulation is a direct result of a significant increase in glycolytic flux, which is needed to meet the increased energy demands of maximal physical activity. This increase in glycolytic flux is accompanied by a decrease in muscle CP content, due to the need to rapidly resynthesise ATP. It has been reported that glycolysis may be stimulated by a decline in CP levels, leading researchers to suggest that phosphofructokinase (PFK), a key glycolytic enzyme, is at least  Adis International Limited. All rights reserved.

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partly inhibited by CP. Therefore, during intense physical activity CP decreases, PFK becomes less inhibited and the rate of glycolysis increases, producing more ATP for active muscle.[26] 5. Creatine Supplementation While the importance and effects of creatine and CP to physical activity have been known for a long period of time, research into creatine supplementation has only occurred in the last decade or so. Harris et al.[6] investigated whether creatine supplementation could increase plasma levels and ultimately increase the total creatine content of skeletal muscle. While normal plasma Cr is between 50 and 100 µmol/L, Harris et al.[6] reported that a 5g dose produced a mean peak plasma concentration of 795 µmol/L after 1 hour, which declined to normal levels over the subsequent 6 to 7 hours. In determining whether this increased plasma concentration would increase total creatine in muscle, the researchers supplemented 17 volunteers with 5g creatine monohydrate, 4 to 6 times a day for 3 or more days. Muscle Cr was measured from freeze dried muscle biopsy samples taken from the vastus lateralis before and after supplementation. Prior to supplementation the mean total creatine content was 126.8 mmol/kg dm, and following supplementation it increased to 148.6 mmol/kg dm. Analysis showed that the increase in total creatine content resulted from an increase in both Crfree and CP, with CP accounting for 20 to 40% of the total increase. No increase in ATP content in muscle was associated with increased CP content. Harris et al.[6] reported that increases in total creatine content varied greatly among volunteers, with the greatest increases in total creatine being observed in volunteers with the lowest initial total creatine content. As part of their study, Harris et al.[6] reported that in 3 volunteers receiving creatine 5g, 6 times a day for 3 days, the amount of the dosage retrieved in the urine was 40% the first day, 61% on day 2 and 68% on day 3. These results suggest that the greatest uptake of creatine into the muscles occurs in the initial stages of supplementation, and that Sports Med 1999 Jul; 28 (1)

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Table I. Studies reporting a significant effect with creatine supplementation Study Soderlund et al.[28]

Greenhaff et al.[29]

n

Dosage

Protocol

Results

8

20g × 6 days

Part I: 5 × 6 sec CE with 30 sec rest Part II: 10 sec CE with 40 sec rest

Part I: increase in CP after 6th bout Part II: increase performance, increase total Cr

8

20g × 5 days

30 sec isometric contraction

Vandenberghe et al.[30]

19

20g × 4 days then Arm flexion test 5g × 28 days

Greenhaff et al.[31]

12

20g × 5 days

Dawson et al.[32]

18 & 22 20g × 5 days

Earnest et al.[33]

10

Kreider et al.[34]

25

Balsom et al.[35]

Increase in total Cr in 5 of 8 Increase in maximum strength, increase in fat free mass

5 × 30 sec knee extensions

Increase in peak torque in bouts 2 and 3

Part I: 10 sec CE Part II: 6 × 6 sec CE with 24 sec rest

Part I: no effect on peak power or total work Part II: increase in peak power and total work

20g × 14 days

Part I: 3 × 30 sec CE with 5 min rest Part II: 1RM bench press Part III: 70% 1RM

Part I: increase in anaerobic power Part II: no effect Part III: increase in number of repetitions

15.75g × 28 days

Bench press, squat, power clean, 12 × 6 sec CE with 30 sec rest

Increase in bench press, no effect on squat and power clean, increase in total lifting volume, increase in CE sets 1 to 5

7

20g × 6 days

Part I: 5 × 6 sec CE with 30 sec rest Part II: 10 sec CE with 40 sec rest Part III: jump

Part I: no effect Part II: increase in performance Part III: no effect

Birch et al.[36]

14

20g × 5 days

3 × 30 sec CE with 4 min rest

Increase in peak and mean power

Bosco et al.[37]

14

20g × 5 days

Part I: 5 and 45 sec jumping Part II: anaerobic speed test

Part I: increase in total work in 45 sec Part II: increase in time

9

25g × 7 days

Part I: 5 × 15 sec CE with 1 min rest Part II: 5 × 1 min CE with 5 min rest

Part I: increase in performance Part II: no effect

10

30g × 6 days

4 × 300m with 4 min rest 4 × 1000m with 3 min rest

Decreased final 300m time Decrease in total and final 1000m time

20g × 5 days

5 sets bench press with 2 min rest, 5 sets jump squats with 2 min rest

Increase in repetitions in all 5 sets of bench press, increase in peak power in all sets of jump squats

Schneider et al.[38] Harris et al.[39] Volek et al.[40]

Earnest et al.[41]

8

20g × 14 days


No effect on peak power, increase in total work

Gordon et al.[42]

17

20g × 10 days

1 and 2 leg CE

Increase in total Cr and CP, increase in performance

0.5 g/kg × 6 days

3 static contractions, 3 × 30 MVC, 4 × 20 MVC, 5 × 10 MVC

Increase in dynamic torque

21g × 9 days

3 × 100m freestyle swim with 60 sec rest, 3 × 20 sec arm ergometer with 60 sec rest

Improved swim time, increased performance

Vandenberghe et al.[43] Grindstaff et al.[44]

9

CE = cycle ergometer; CP = creatine phosphate concentration; Cr = total creatine concentration; MVC = maximum voluntary; n = number of participants; RM = repetition maximum.

there is a limit to the amount of creatine which can be stored in muscles. They concluded that 155 mmol/kg dm likely represented the maximum limit for total creatine content, using supplement doses of 20 to 30 g/day. Harris et al.[6] also examined the effects of exercise on the uptake of creatine into muscle. Five volunteers performing 1 hour of unilateral cycling  Adis International Limited. All rights reserved.

ergometry (the opposing leg served as control) reported increasing total creatine content from 118.1 mmol/kg dry weight prior to supplementation, to 148.5 in the control leg, and 162.2 in the exercised leg. These results suggest that exercise seems to enhance the local uptake of creatine into muscle. The authors proposed that this increase was due to increased blood flow into the exercised muscles Sports Med 1999 Jul; 28 (1)


compared to the control, or a change in the transport kinetics of creatine across the muscle cell membrane. There is also evidence to suggest that carbohydrate ingestion may also augment skeletal muscle creatine accumulation. Green et al.[27] reported that 93g of simple carbohydrate in solution taken 30 minutes following creatine ingestion resulted in a 60% greater increase in total Cr, a process likely mediated by insulin. Other studies that examined the effects of creatine supplementation include a study by Soderlund et al.,[28] who reported a total creatine content increase of 24.6 mmol/kg dm. Greenhaff et al.[29] reported that in 5 of 8 volunteers, creatine supplementation significantly increased total muscle creatine content, ranging from 19 to 35 mmol/kg dm. However, creatine supplementation had little effect in the other 3 volunteers, producing an increase of only 8 to 9 mmol/kg dm. These results led researchers to propose the notion of responders and nonresponders to creatine supplementation. Greenhaff et al.[29] reported that all of those who responded to creatine ingestion with increased muscle creatine content had initial concentrations of < 120 mmol/kg dm, while those who did not respond had initial mean concentrations of > 130 mmol/kg dm. These results may explain many of the equivocal results reported in the literature, and also explain why the 2 vegetarians in the Harris et al.[6] study reported the largest increases in total creatine content (table I). In a study using 2 dose protocols (20 g/day for 6 days and 3 g/day for 28 days), Hultman et al.[45] reported that both doses resulted in a similar increase in total creatine content. This study also reported that these elevated creatine levels could be maintained with supplementation of only 2 g/day. However, in the absence of this continual supplementation muscle Cr gradually declined, such that 30 days after cessation of supplementation muscle concentrations were no different than prior to creatine ingestion. The study concluded that there are 2 equally effective means of attaining elevated muscle Cr. A second study[30] examining the effects of  Adis International Limited. All rights reserved.

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long term creatine use reported a significant increase in maximal strength and fat free mass following a supplementation procedure involving 4 days of high intake (20 g/day) followed by a low dose of 5 g/day during the 10-week training period. Similarly to Hultman et al.,[45] this study found that cessation of intake returned Cr to pre-supplementation levels within 4 weeks. 5.1 Creatine Supplementation and CP Resynthesis

Greenhaff et al.[31] examined the effects of creatine supplementation 20 g/day for 5 days on CP resynthesis following intense isometric contractions, and reported that after 2 minutes of recovery, the supplement group had CP values 20% greater than the placebo group. This suggested an accelerated rate of CP resynthesis following creatine supplementation. These same researchers also reported that during the first minute of recovery, CP resynthesis was similar between placebo and creatine ingestion groups. However, during the second minute of recovery CP resynthesis was 42% greater in the creatine group. While much of the attention has focused on initial CP concentrations, Greenhaff et al.[29] suggested that the real value of creatine supplementation may lie in the increase in Crfree. While the Michaelis-Menten constant (Km) values of CPK for ATP and ADP are quite low (approximately 0.6 and 1 mmol/L, respectively), the Km of CPK for creatine is comparatively high, close to 19 mmol/L. Following maximal exercise the initial concentration of Crfree exceeds the Km, allowing for unhindered resynthesis of CP. But as the concentration of Crfree decreases toward 19 mmol/L, Crfree may begin to be the determining factor in the rate of CP resynthesis. Therefore, with creatine ingestion the concentration of Crfree is increased, allowing for greater amounts of resynthesis prior to the concentration of Crfree approaching 19 mmol/L. This increase in Crfree concentration was thus reported to be responsible for the 30% greater concentration of CP following 2 minutes of recovery. Sports Med 1999 Jul; 28 (1)

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5.2 Side Effects

Increase in body mass is a common side effect of large doses of creatine ingestion (20 to 30g).[28,29,32-34,46,47] Most of the published studies involve creatine supplementation over a relatively short period of time, usually less than a week. Poortmans et al.[48] investigated the effects of high dose (20 g/day for 5 days) creatine supplementation on renal responses and reported no detrimental effects. Very little data exist on the effects of long term creatine supplementation on body mass. In a study using 20 g/day for 28 days, Earnest et al.[33] reported a mean body mass increase of 3.8kg. Other studies using protocols involving 20 to 30 g/day for ≤ 7 days reported mean body mass increases of between 0.9 and 1.8kg. These increases in body mass are generally reported to be due to water retention[3] since creatine may act to alter the hydration status of the muscle cells, resulting in increased mass. However, others suggest that creatine may be involved in muscle protein synthesis, acting as the chemical signal coupling with increased muscle activity increases contractile protein synthesis.[49] The exact mechanism responsible for an increase in body mass is yet to be fully explained, and thus requires further research. While most research suggests that there appear to be no dangerous side effects involved with creatine supplementation, a recent report[50] has suggested that creatine supplementation may be responsible for a deterioration in renal function. However, this report involved a patient with glomerulosclerosis and was based on circumstantial evidence. Further research is required to determine whether a cause-effect relationship actually exists. 6. Creatine Supplementation and Exercise Performance 6.1 Incremental and Endurance Exercise

The effects of creatine supplementation on incremental and endurance type exercises have been studied by various researchers. Stoud et al.[47] reported no measurable effect on respiratory gas ex Adis International Limited. All rights reserved.

change or blood lactate concentrations using a continuous incremental test, running at 10 km/h on a treadmill at workloads of 50, 60, 70, 80 and 90% . VO2max, with 6 minutes at each workload, and using a creatine dose of 20 g/day for 5 days. In another study[46] involving creatine supplementation of 20 g/day for 6 days, volunteers showed no improvement in performance time of a 6km cross-country run. In fact, running time was actually increased following supplementation, likely due to the increased body mass associated with creatine ingestion. These studies suggest that creatine supplementation is not beneficial for incremental or endurance type activities and may even be detrimental. These results appear to be logical since CP is not considered a limiting factor for performance in these types of exercises. 6.2 High Intensity Exercises

The idea of delaying fatigue and increasing the rate of recovery has great implications for sport performance. The ability to delay fatigue for a short time longer or recover more quickly is often what separates the elite athletes from the good athletes. It is with this in mind that a vast amount of research involving high intensity exercise has taken place within the last 5 to 7 years. Greenhaff et al.[31] reported that creatine supplementation of 20 g/day for 5 days resulted in an increased peak muscle torque in 5 bouts of 30 maximal voluntary isokinetic knee extensions, separated by 1 minute rest intervals. Increased peak muscle torque was reported in the final 10 concentrations of bout number 1, and throughout bout numbers 2, 3 and 4 and contractions 11 to 20 of bout number 5. Balsom et al.[35] and Soderlund et al.[28] both carried out studies involving 6 days of 20 g/day creatine supplementation, using a protocol of 5 bouts of 6 seconds of maximal cycling separated by 30 seconds of rest, followed by a 40-second rest and a sixth exercise bout lasting 10 seconds. Both studies reported a higher CP concentration following the fifth 6-second bout in the creatine trials compared to the control trials, as well as volunteers being better able to maintain a target speed near the Sports Med 1999 Jul; 28 (1)


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Table II. Studies reporting no effect from creatine supplementation Study

Dosage

Protocol

Stoud et al.[47]

8

20g × 5 days

Running at 10 km/h at 50, 60, 70, 80, . 90% VO2max

Barnet et al.[51]

17

4 × 70 mg/kg

5 × 10 sec CE with 30 sec rest, 2 × 10 sec with 5 min rest

No effect on performance

6

20g × 5 days

4 × 1 min + 1 to exhaustion at 115 to . 125% VO2max


Febbraio et al.[52]

n

Result . No effect on RER and VO2max

Mujika et al.[53]

20

20g × 5 days

25, 50, 100m swims

No effect on performance time

Odland et al.[54]

9

20g × 3 days

30 sec Wingate test


Terrillion et al.[55]

12

20g × 5 days

2 × 700m sprints with 2 min rest


Burke et al.[56]

32

20g × 5 days

25, 50, 100m swims

No effect on performance time

Cooke et al.[57]

12

20g × 5 days


No effect on peak power, time to peak power, total work, or fatigue index

Harridge et al.[58]

8

20g × 6 days

2 min knee and ankle extensions at 1/sec

No effect on torque

Redondo et al.[59]

18

25g × 7 days

3 × 60m sprints with 2 min rest


Thompson et al.[60]

10

2 g/day × 6 weeks

100 and 400m swims


CE = cycle ergometry; n = number of participants; RER = respiratory exchange ratio.

end of the 10-second exercise bout. These studies also reported a decrease in muscle lactate, a finding not supported by many other studies measuring lactate.[31-33,36-38,51-55] Bosco et al.[37] reported no difference in lactate accumulation during a 5- and 45-second continuous jumping test between a creatine group and placebo group, even though the creatine group reported a significant enhancement of performance in the 45-second jumping test. This study did, however, report a 15% increase in lactate accumulation in the creatine group between their pre- and post-ingestion trials following an anaerobic speed test. There was no difference in pre and post values for the placebo group. The case for the role of creatine supplementation in aiding recovery rate is helped by the results of a study by Schneider et al.[38] Their protocol consisted of 2 parts, part 1 consisting of 5 15-second bouts of maximal cycling with 1 minute rest intervals, and part 2 involving 5 1-minute bouts of maximal cycling with 5-minute rest intervals. The study reported that the creatine trials resulted in a significant increase in work performed during each of the 15-second bouts compared to placebo trials, whereas work performed during the 1-minute bouts was not significantly increased in the creatine trials.  Adis International Limited. All rights reserved.

The researchers attributed the increased performance in the 15-second bouts to higher initial CP levels as well as an increased resynthesis rate. This increased rate or resynthesis following creatine supplementation is also cited by Harris et al.,[39] who reported a decrease in running time in the final of 4 bouts of 300m, separated by 4-minute rest intervals, following creatine ingestion, compared to placebo ingestion. This study also reported a significant decrease in total running time in the creatine group, while running 4 × 1000m, as well as decreased final 1000m run time. Dawson et al.[32] reported no significant differences in peak power or total work during 10 seconds of maximal cycle ergometer sprints between creatine and placebo groups. However, they did report significant differences between groups during repeated bouts with limited rest. While much of the research into the effects of creatine supplementation has involved running or cycling protocols, much of the marketing of the packaged product is geared toward weight training. To date, few studies of creatine supplementation and weight training have been conducted. Earnest et al.[33] used 10 experienced weightlifters and a protocol involving 3 consecutive 30-second Wingate bike tests, 1 repetition maximum (RM) free Sports Med 1999 Jul; 28 (1)

58

weight bench press, and 70% of the bench press 1RM until fatigue. Reported results showed that total anaerobic work for all Wingate tests were significantly higher during the creatine trials, while no changes were noted in the placebo trials. Bench press 1RM was reported to increase by 6% in the creatine group. However, when this was corrected for body weight, no significant differences were noted because of the significant increase in body weight in the creatine group. Total lifting volume was significantly higher in the creatine group, which performed 26% more lifting repetitions. A second study[40] examining the effects of creatine supplementation on weight training involved 5 sets of bench press to exhaustion with 2-minute rest intervals, and 5 sets of jump squats with 2-minute rest intervals. The creatine group reported an increase in the number of repetitions completed during all 5 sets of bench press as well as reporting an increase in peak power during all 5 sets of jump squats, compared to the placebo group. Kreider et al.[34] found that creatine had no effect on squat and power clean exercises, but did significantly affect bench press and sum of bench press, squat, and power clean lifting volume. While many studies support the idea that creatine supplementation can enhance exercise performance, others have found no significant effect (table II). Cooke et al.[57] measured power output during 15 seconds of maximal cycling sprints against a constant load, and reported no significant differences between groups for peak power, time to peak power or total work. Similarly, Odland et al.[54] reported no significant differences in mean peak 10second power output, mean peak 30-second power output, percent fatigue or postexercise lactate accumulation between groups during 30-second maximal cycling sprints (Wingate test). Interestingly, this study also reported no significant differences in CP concentration or total Cr between groups, despite using a dose of 20 g/day for 3 days. The volunteers in this group may by chance have been predominantly nonresponders. Investigation of the effects of creatine supplementation on swim sprint performance has also re Adis International Limited. All rights reserved.

Demant & Rhodes

ported no significant effects on 25, 50 or 100m sprints.[53,56] However, Mujika et al.[53] did report a decrease in plasma ammonia concentration following 50 and 100m sprints in creatine trials, but only in the 50m sprint in placebo trials. The decrease in plasma ammonia concentrations corresponds to other studies which also reported a decrease in plasma ammonia.[31,56] Greenhaff et al.[31] explained the decrease in ammonia concentration compared to placebo trials as a more efficient ADP rephosphorylation after creatine supplementation, since ammonia accumulation is a marker for muscle adenine nucleotide loss during maximal exercise. The decline in ammonia concentration in creatine groups supports the idea of greater CP availability and utilisation during exercise. Several other studies have also shown that creatine supplementation failed to significantly affect running time in short distance or middle distance sprints.[55,59] Terrillion et al.[55] reported that creatine supplementation in 12 competitive runners had no effect on 700m maximal running times, compared to placebo trials. Redondo et al.[59] reported that creatine supplementation in 18 collegiate field hockey players had no effect on 3 sets of 60m sprints separated by 2-minute rest intervals. 7. Conclusions While creatine has been a subject of research for over a century, its prominence in the exercise scene is a fairly new phenomenon. Creatine is a vital component in the short term, maximal intensity energy system, responsible for fuelling activities such as the 100m dash, the 25m swim sprint, power activities and strength training. While daily turnover rates are normally met via exogenous intake and endogenous synthesis, creatine supplementation has been shown to dramatically increase the amount of creatine stored in skeletal muscle. However, this may not be the case for all individuals, since research has suggested that while some respond to creatine supplementation, others can be considered nonresponders. It appears that individuals with normally low Cr, such as vegetarians, seem to reSports Med 1999 Jul; 28 (1)


spond the most, while those with higher initial concentrations often report no significant changes with supplementation. Creatine supplementation of 20 to 30g per day for 3 days or longer is believed to enhance exercise performance in 2 ways. Firstly, by increasing the initial amounts of CP in the muscle, thereby providing a greater initial source of energy, and secondly, by providing more Crfree, thereby aiding the resynthesis rate of CP during recovery. Although the claims are great, the verdict is still out. While many studies report significant effects, others fail to show a difference between creatine and placebo groups. It appears that in those that respond to supplementation, an increased rate of resynthesis during recovery aids in attaining improved performances. However, in single sport-specific events such as swim or run sprints, there are no ergogenic benefits. This also holds true for both incremental and endurance type exercises, where creatine supplementation may actually be detrimental. The only side effect associated with short term creatine supplementation is an increase in body mass, which is largely attributed to water retention. Although some researchers have suggested that creatine may be involved in promoting protein synthesis in skeletal muscle and thus be considered an anabolic agent, more research is needed in this area, especially as it pertains to strength training. The quest to determine whether creatine is a viable performance-enhancing supplement has greatly increased our knowledge of its storage within the body, as well as its mechanisms of action. While much has been uncovered, much more is still to be investigated in order to make concrete conclusions about the exact effect of creatine on performance. References 1. Needham DM. Machina carnis: the biochemistry of muscular contraction in its historical development. Cambridge: Cambridge University Press, 1971 2. Hunter A. Monographs of biochemistry: creatine and creatinine. London: Longmans, Green and Co., 1928 3. Balsom PD, Soderlund K, Sjordin B, et al. Skeletal muscle metabolism during short duration high-intensity exercise: influence of creatine supplementation. Acta Physiol Scand 1995; 154: 303-10 4. Hultman E, Bergstrom T, Anderson NM. Breakdown and resynthesis of phosphorylcreatine and adenosine triphosphate in

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59

5. 6.

7.

8. 9.

10. 11.

12.

13.

14. 15. 16.

17.

18.

19.

20.

21.

22. 23.

24.

25. 26.

connection with muscular work in man. Scand J Clin Lab Invest 1967; 19: 56-66 Devlin TM. Textbook of biochemistry: with clinical correlations. New York: Wiley-Liss, 1992 Harris RC, Soderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci 1992; 83: 367-74 Guimbal C, Kilimann MW. A Na+-dependent creatine transporter in rabbit brain, muscle, heart and kidney. J Biol Chem 1993; 268: 8418-21 Haugland RB, Chang DT. Insulin effect on creatine transport in skeletal muscle. Proc Soc Exp Biol Med 1975; 148: 1-4 Odoom JE, Kemp GJ, Radda GK. Control of intracellular creatine concentration in a mouse myoblast cell line [abstract]. Biochem Soc Trans 1993; 21: 441S Gerber GB, Gerber G, Koszalka TR, et al. Creatine metabolism in vitamin E deficiency in rats. Am J Physiol 1962; 202: 453-60 Heymsfield SB, Arteaga C, McManus C, et al. Measurement of muscle mass in humans: validity of the 24-hour urinary creatinine method. Am J Clin Nutr 1983; 37: 478-94 Harris RC, Viru M, Greenhaff PL, et al. The effects of oral creatine supplementation on running performance during maximal short term exercise in man [abstract]. J Physiol 1993; 467: 74P Crim MC, Calloway DH, Margen S. Creatine metabolism in men: creatine pool size and turnover in relation to creatine intake. J Nutr 1976; 106: 371-81 Bjornsson TD. Use of serum creatinine concentration to determine renal function. Clin Pharmacokinet 1979; 4: 200-22 Walker JB. Metabolic control of creatine biosynthesis: effect of dietary creatine. J Biol Chem 1960; 235: 2357-61 Delanghe J, DeSlypere JP, Debuyzere M, et al. Normal reference values for creatine, creatinine and carnitine are lower in vegetarians. Clin Chem 1989; 35: 1802-3 Tesch PA, Thorsson A, Fujitsuka N. Creatine phosphate in fiber types of skeletal muscle before and after exhaustive exercise. J Appl Physiol 1989; 66 (4): 1756-9 Essen B. Studies on the regulation of metabolism in human skeletal muscle using intermittent exercise as an experimental model. Aust J Sci Med Sport 1978; 454: 1-64 Edstrom L, Hultman E, Sahlin K, et al. The contents of highenergy phosphates in different fibre types in skeletal muscles from rat, guinea-pig and man. J Physiol 1992; 332: 47-58 McArdle WD, Katch FI, Katch VL. Exercise physiology: energy, nutrition and human performance. Philadelphia: Lea & Febiger, 1991 Moeller P, Bergstrom J, Furst P, et al. Effects of aging on energy rich phosphogens in human skeletal muscle. Clin Sci 1980; 58: 553-5 Fosberg AM, Nillson E, Werneman JM. Muscle composition in relation to age and sex. Clin Sci 1991; 81: 249-56 Gariod L, Binzoni T, Feretti G. Standardization of 31-phosphorus nuclear magnetic resonance spectroscopy determinations of high-energy phosphates in humans. Eur J Appl Physiol 1994; 68: 107-10 Bernus G, Gonzalez de Suso JM, Alonso J, et al. 31P-MRS of quadriceps reveals quantitative differences between sprinters and long-distance runners. Med Sci Sports Exerc 1993; 25: 479-84 Bessman SP, Geiger P. Transport on energy in muscle: the phosphorylcreatine shuttle. Science 1981; 211 (4481): 448-52 Volek JS, Kraemer WJ. Creatine supplementation: its effect on human muscular performance and body composition. J Stren Cond Res 1996; 10 (3): 200-10

Sports Med 1999 Jul; 28 (1)

60

27. Green AL, Hultman E, MacDonald IA, et al. Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. Am J Physiol 1996; 271: E821-6 28. Soderlund K, Balsom PD, Ekblom B. Creatine supplementation and high intensity exercise: influence on performance and muscle metabolism. Clin Sci 1994; 87 Suppl.: 120 29. Greenhaff PL, Bodin K, Soderlund K, et al. Effects of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am J Physiol 1994; 266: E725-30 30. Vandenberghe K, Goris M, Van Hecke P, et al. Long-term creatine intake is beneficial to muscle performance during resistance training. J Appl Physiol 1997; 83 (6): 2055-63 31. Greenhaff PL, Casey A, Short AH, et al. Influence of oral creatine supplementation of muscle torque during repeated bouts of maximal voluntary exercise in man. Clin Sci 1993; 84: 565-71 32. Dawson B, Cutler M, Moody A, et al. Effects of oral creatine loading on single and repeated maximal short sprints. Aust J Sci Med Sport 1995; 27 (3): 56-61 33. Earnest CP, Snell PG, Rodriguez R, et al. The effect of creatine monohydrate ingestion on anaerobic power indices, muscular strength and body composition. Acta Physiol Scand 1995; 153: 207-9 34. Kreider RB, Ferreira M, Wilson M, et al. Effects of creatine supplementation on body composition, strength, and sprint performance. Med Sci Sports Exerc 1998; 30 (1): 73-82 35. Balsom PD, Soderlund K, Ekblom B. Creatine in humans with special reference to creatine supplementation. Sports Med 1994; 18: 268-80 36. Birch R, Noble P, Greenhaff PL. The influence of dietary creatine supplementation on performance during repeated bouts of maximal isokinetic cycling in man. Eur J Appl Physiol 1994; 69: 268-70 37. Bosco C, Tihanyi J, Pucspk J, et al. Effect of oral creatine supplementation on jumping and running performance. Int J Sports Med 1997; 18: 369-72 38. Schneider DA, McDonough PJ, Fadel PJ, et al. Creatine supplementation and the total work performed during 15s and 1 min bouts of maximal cycling. Aust J Sci Med Sport 1997; 29 (3): 65-8 39. Harris RC, Hultman E, Nordesjo LO. Glycogen, glycolytic intermediates and high-energy phosphates determined in biopsy samples of musculus quadriceps femoris of man at rest: methods and variance of values. Scand J Clin Lab Invest 1974; 33: 109-20 40. Volek JS, Kraemer WJ, Bush JA, et al. Creatine supplementation enhances muscular performance during high intensity resistance exercise. J Am Diet Assoc 1997; 97: 765-70 41. Earnest CP, Snell PG, Mitchell TL, et al. Effects of creatine monohydrate ingestion on peak anaerobic power, capacity, and fatigue index. Med Sci Sports Exerc 1994; 26: S39 42. Gordon A, Hultman E, Kaijser L, et al. Creatine supplementation in chronic heart failure increases skeletal creatine phosphate and muscle performance. Cardio Res 1995; 30: 413-8 43. Vandenberghe K, Gillis N, Van Leemputte M, et al. Caffeine counteracts the ergogenic action of muscle creatine loading. J Appl Physiol 1996; 80 (2): 452-7 44. Grindstaff PD, Kreider RB, Bishop R, et al. Effects of creatine supplementation on repetitive sprint performance and body

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Demant & Rhodes

45. 46.

47.

48.

49.

50. 51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

composition in competitive swimmers. Int J Sport Nutr 1997; 7: 330-46 Hultman E, Soderlund K, Timmons JA, et al. Muscle creatine loading in men. J Appl Physiol 1996; 81 (1): 232-7 Balsom PD, Harridge SDR, Soderlund K. Creatine supplementation per se does not enhance endurance exercise performance. Acta Physiol Scand 1993; 149: 521-3 Stoud MA, Holliman D, Bell D, et al. Effects of oral creatine supplementation on respiratory gas exchange and blood lactate accumulation during steady-state incremental exercise and recovery in man. Clin Sci 1994; 87: 707-10 Poortmans JR, Auquier H, Renaut V, et al. Effects of short-term creatine supplementation on renal responses in men. Eur J Appl Physiol 1997; 76 (6): 566-7 Ingwall JS, Weiner CD, Morales MF, et al. Specificity of creatine in the control of muscle protein synthesis. J Cell Biol 1974; 63: 145-51 Prichard NR, Kalra PA. Renal dysfunction accompanying oral creatine supplements. Lancet 1998; 351: 1252-3 Barnet C, Hinds M, Jenkins DJ. Effects of oral creatine supplementation on multiple sprint cycle performance. Aust J Sci Med Sport 1996; 28 (1): 35-9 Febbraio MA, Flanagan TR, Snow RJ, et al. Effect of creatine supplementation on intramuscular Tcr, metabolism and performance during intermittent, supramaximal exercise in humans. Acta Physiol Scand 1995; 155 (4): 387-95 Mujika I, Chatard J, Lacoste L, et al. Creatine supplementation does not improve sprint performance in competitive swimmers. Med Sci Sports Exerc 1996; 28 (11): 1435-41 Odland LM, MacDougall JD, Tarnopolsky M, et al. The effects of oral Cr supplementation on muscle [Pcr] and power output during a short-term maximal cycling task. Med Sci Sports Exerc 1997; 29 (2): 211-9 Terrillion KA, Kolkhorst FW, Dolgener FA, et al. Effects of creatine supplementation on two 700m maximal running bouts. Int J Sport Nutr 1997; 7: 138-43 Burke LM, Pyne DB, Telford RD. Effect of oral creatine supplementation on single-effort sprint performance in elite swimmers. Int J Sport Nutr 1996; 6: 22-33 Cooke WH, Grandjean PW, Barnes WS. Effects of oral creatine supplementation on power output and fatigue during bicycle ergometry. J Appl Physiol 1995; 78 (2): 670-3 Harridge SDR, Balsom PD, Soderlund K. Creatine supplementation and electrically evoked human muscle fatigue. Clin Sci 1994; 87 Suppl.: 124 Redondo DR, Dowling EA, Graham BL, et al. The effects of oral creatine monohydrate on running velocity. Int J Sport Nutr 1996; 6: 213-21 Thompson CH, Kemp GJ, Sanderson AL, et al. Effects of creatine on aerobic and anaerobic metabolism is skeletal muscle in swimmers. Br J Sports Med 1996; 30: 222-5

Correspondence and reprints: Dr E.C. Rhodes, University of British Columbia, School of Human Kinetics, 210-6081 University Boulevard, Vancouver, BC V6T 1Z1, Canada. E-mail: [email protected]

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