by Bret Contreras November 04, 2014
Creatine is one of the few supplements that has stood the test of time. I can recall first taking it when I was in high school over 20 years ago. I’m pretty sure it’s the most well-research supplement in the literature, with thousands upon thousands of articles on the topic. HERE is a Wikipedia link to creatine in case you’d like to learn the basics. Over the years, I’ve stumbled across some interesting research on creatine. I decided to compile some of these study abstracts together into an article. When sifting through the entire body of research, it seems that creatine does not enhance testosterone or growth hormone output (one study showed increased growth hormone, but several others have shown no effect), does not work as well in the elderly as it does with younger subjects, does not reduce muscle damage (one study showed that it did, but several others showed that it did not), does not improve the plasma-lipid ratio during aerobic training, and does not alter insulin sensitivity.
However, creatine does indeed lead to some very favorable outcomes. It’s also very safe and well-tolerated. In the abstracts below, you will note that creatine:
Creatine monohydrate has become the supplement of choice for many athletes striving to improve sports performance. Recent data indicate that athletes may not be using creatine as a sports performance booster per se but instead use creatine chronically as a training aid to augment intense resistance training workouts. Although several studies have evaluated the combined effects of creatine supplementation and resistance training on muscle strength and weightlifting performance, these data have not been analyzed collectively. The purpose of this review is to evaluate the effects of creatine supplementation on muscle strength and weightlifting performance when ingested concomitant with resistance training. The effects of gender, interindividual variability, training status, and possible mechanisms of action are discussed. Of the 22 studies reviewed, the average increase in muscle strength (1, 3, or 10 repetition maximum [RM]) following creatine supplementation plus resistance training was 8% greater than the average increase in muscle strength following placebo ingestion during resistance training (20 vs. 12%). Similarly, the average increase in weightlifting performance (maximal repetitions at a given percent of maximal strength) following creatine supplementation plus resistance training was 14% greater than the average increase in weightlifting performance following placebo ingestion during resistance training (26 vs. 12%). The increase in bench press 1RM ranged from 3 to 45%, and the improvement in weightlifting performance in the bench press ranged from 16 to 43%. Thus there is substantial evidence to indicate that creatine supplementation during resistance training is more effective at increasing muscle strength and weightlifting performance than resistance training alone, although the response is highly variable.
A large number of studies have been published on creatine supplementation over the last decade. Many studies show that creatine supplementation in conjunction with resistance training augments gains in muscle strength and size. The underlying physiological mechanism(s) to explain this ergogenic effect remain unclear. Increases in muscle fiber hypertrophy and myosin heavy chain expression have been observed with creatine supplementation. Creatine supplementation increases acute weightlifting performance and training volume, which may allow for greater overload and adaptations to training. Creatine supplementation may also induce a cellular swelling in muscle cells, which in turn may affect carbohydrate and protein metabolism. Several studies point to the conclusion that elevated intramuscular creatine can enhance glycogen levels but an effect on protein synthesis/degradation has not been consistently detected. As expected there is a distribution of responses to creatine supplementation that can be largely explained by the degree of creatine uptake into muscle. Thus, there is wide interest in methods to maximize muscle creatine levels. A carbohydrate or carbohydrate/protein-induced insulin response appears to benefit creatine uptake. In summary, the predominance of research indicates that creatine supplementation represents a safe, effective, and legal method to enhance muscle size and strength responses to resistance training.
Creatine has become a popular nutritional supplement among athletes. Recent research has also suggested that there may be a number of potential therapeutic uses of creatine. This paper reviews the available research that has examined the potential ergogenic value of creatine supplementation on exercise performance and training adaptations. Review of the literature indicates that over 500 research studies have evaluated the effects of creatine supplementation on muscle physiology and/or exercise capacity in healthy, trained, and various diseased populations. Short-term creatine supplementation (e.g. 20 g/day for 5-7 days) has typically been reported to increase total creatine content by 10-30% and phosphocreatine stores by 10-40%. Of the approximately 300 studies that have evaluated the potential ergogenic value of creatine supplementation, about 70% of these studies report statistically significant results while remaining studies generally report non-significant gains in performance. No study reports a statistically significant ergolytic effect. For example, short-term creatine supplementation has been reported to improve maximal power/strength (5-15%), work performed during sets of maximal effort muscle contractions (5-15%), single-effort sprint performance (1-5%), and work performed during repetitive sprint performance (5-15%). Moreover, creatine supplementation during training has been reported to promote significantly greater gains in strength, fat free mass, and performance primarily of high intensity exercise tasks. Although not all studies report significant results, the preponderance of scientific evidence indicates that creatine supplementation appears to be a generally effective nutritional ergogenic aid for a variety of exercise tasks in a number of athletic and clinical populations.
Creatine supplementation (CS) has been reported to increase body mass and improve performance in high-intensity, short-duration exercise tasks. Research on CS, most of which has come into existence since 1994, has been the focus of several qualitative reviews, but only one meta-analysis, which was conducted with a limited number of studies.
This study compared the effects of CS on effect size (ES) for body composition (BC) variables (mass and lean body mass), duration and intensity (< or = 30 s, [ATP-PCr = A]; 30-150 s [glycolysis = G]; >150 s, [oxidative phosphorylation = O]) of the exercise task, type of exercise task (single, repetitive, laboratory, field, upper-body, lower-body), CS duration (loading, maintenance), and subject characteristics (gender, training status).
A search of MEDLINE and SPORTDiscus using the phrase “creatine supplementation” revealed 96 English-language, peer-reviewed papers (100 studies), which included randomized group formation, a placebo control, and human subjects who were blinded to treatments. ES was calculated for each body composition and performance variable.
Small, but significant (ES > 0, p < or = .05) ES were reported for BC (n=163, mean +/- SE=0.17 +/- 0.03), ATP-PCr (n=17, 0.24 +/- 0.02), G (n=135, 0.19 +/- 0.05), and O (n=69, 0.20 +/- 0.07). ES was greater for change in BC following a loading-only CS regimen (0.26 +/- 0.03, p=.0003) compared to a maintenance regimen (0.04 +/- 0.05), for repetitive-bout (0.25 +/- 0.03,p=.028) compared to single-bout (0.18 +/- 0.02) exercise, and for upper-body exercise (0.42 +/- 0.07, p<.0001) compared to lower (0.21 +/- 0.02) and total body (0.13 +/- 0.04) exercise. ES for laboratory-based tasks (e.g., isometric/isotonic/isokinetic exercise, 0.25 +/- 0.02) were greater (p=.014) than those observed for field-based tasks (e.g., running, swimming, 0.14 +/- 0.04). There were no differences in BC or performance ES between males and females or between trained and untrained subjects.
ES was greater for changes in lean body mass following short-term CS, repetitive-bout laboratory-based exercise tasks < or = 30 s (e.g., isometric, isokinetic, and isotonic resistance exercise), and upper-body exercise. CS does not appear to be effective in improving running and swimming performance. There is no evidence in the literature of an effect of gender or training status on ES following CS.
Creatine monohydrate (Cr) is perhaps one of the most widely used supplements taken in an attempt to improve athletic performance. The aim of this review is to update, summarise and evaluate the findings associated with Cr ingestion and sport and exercise performance with the most recent research available. Because of the large volume of scientific literature dealing with Cr supplementation and the recent efforts to delineate sport-specific effects, this paper focuses on research articles that have been published since 1999.Cr is produced endogenously by the liver or ingested from exogenous sources such as meat and fish. Almost all the Cr in the body is located in skeletal muscle in either the free (Cr: approximately 40%) or phosphorylated (PCr: approximately 60%) form and represents an average Cr pool of about 120-140 g for an average 70 kg person. It is hypothesised that Cr can act though a number of possible mechanisms as a potential ergogenic aid but it appears to be most effective for activities that involve repeated short bouts of high-intensity physical activity. Additionally, investigators have studied a number of different Cr loading programmes; the most common programme involves an initial loading phase of 20 g/day for 5-7 days, followed by a maintenance phase of 3-5 g/day for differing periods of time (1 week to 6 months). When maximal force or strength (dynamic or isotonic contractions) is the outcome measure following Cr ingestion, it generally appears that Cr does significantly impact force production regardless of sport, sex or age. The evidence is much more equivocal when investigating isokinetic force production and little evidence exists to support the use of Cr for isometric muscular performance. There is little benefit from Cr ingestion for the prevention or suppression of muscle damage or soreness following muscular activity. When performance is assessed based on intensity and duration of the exercises, there is contradictory evidence relative to both continuous and intermittent endurance activities. However, activities that involve jumping, sprinting or cycling generally show improved sport performance following Cr ingestion. With these concepts in mind, the focus of this paper is to summarise the effectiveness of Cr on specific performance outcomes rather than on proposed mechanisms of action. The last brief section of this review deals with the potential adverse effects of Cr supplementation. There appears to be no strong scientific evidence to support any adverse effects but it should be noted that there have been no studies to date that address the issue of long-term Cr usage.
During the past decade, the nutritional supplement creatine monohydrate has been gaining popularity exponentially. Introduced to the general public in the early 1990s, shortly after the Barcelona Olympic Games, creatine (Cr) has become one of the most widely used nutritional supplements or ergogenic aids, with loading doses as high as 20-30 g·day(-1) for 5-7 days typical among athletes. This paper reviews the available research that has examined the potential ergogenic value of creatine supplementation (CrS) on exercise performance and training adaptations. Short-term CrS has been reported to improve maximal power/strength, work performed during sets of maximal effort muscle contractions, single-effort sprint performance, and work performed during repetitive sprint performance. During training CrS has been reported to promote significantly greater gains in strength, fat free mass, and exercise performance primarily of high intensity tasks. However, not all studies demonstrate a beneficial effect on exercise performance, as CrS does not appear to be effective in improving running and swimming performance. CrS appears to pose no serious health risks when taken at doses described in the literature and may enhance exercise performance in individuals that require maximal single effort and/or repetitive sprint bouts.
Creatine is one of the most popular and widely researched natural supplements. The majority of studies have focused on the effects of creatinemonohydrate on performance and health; however, many other forms of creatine exist and are commercially available in the sports nutrition/supplement market. Regardless of the form, supplementation with creatine has regularly shown to increase strength, fat free mass, and muscle morphology with concurrent heavy resistance training more than resistance training alone. Creatine may be of benefit in other modes of exercise such as high-intensity sprints or endurance training. However, it appears that the effects of creatine diminish as the length of time spent exercising increases. Even though not all individuals respond similarly to creatine supplementation, it is generally accepted that its supplementationincreases creatine storage and promotes a faster regeneration of adenosine triphosphate between high intensity exercises. These improved outcomes will increase performance and promote greater training adaptations. More recent research suggests that creatine supplementation in amounts of 0.1 g/kg of body weight combined with resistance training improves training adaptations at a cellular and sub-cellular level. Finally, although presently ingesting creatine as an oral supplement is considered safe and ethical, the perception of safety cannot be guaranteed, especially when administered for long period of time to different populations (athletes, sedentary, patient, active, young or elderly).
Creatine monohydrate is a dietary supplement that increases muscle performance in short-duration, high-intensity resistance exercises, which rely on the phosphocreatine shuttle for adenosine triphosphate. The effective dosing for creatine supplementation includes loading with 0.3 g·kg·d for 5 to 7 days, followed by maintenance dosing at 0.03 g·kg·d most commonly for 4 to 6 wk. However loading doses are not necessary to increase the intramuscular stores of creatine. Creatine monohydrate is the most studied; other forms such as creatine ethyl ester have not shown added benefits.Creatine is a relatively safe supplement with few adverse effects reported. The most common adverse effect is transient water retention in the early stages of supplementation. When combined with other supplements or taken at higher than recommended doses for several months, there have been cases of liver and renal complications with creatine. Further studies are needed to evaluate the remote and potential future adverse effects from prolonged creatine supplementation.
Our purpose was to assess muscular adaptations during 6 weeks of resistance training in 36 males randomly assigned to supplementation with whey protein (W; 1.2 g/kg/day), whey protein and creatine monohydrate (WC; 0.1 g/kg/day), or placebo (P; 1.2 g/kg/day maltodextrin). Measures included lean tissue mass by dual energy x-ray absorptiometry, bench press and squat strength (1-repetition maximum), and knee extension/flexion peak torque. Lean tissue mass increased to a greater extent with training in WC compared to the other groups, and in the W compared to the P group (p < .05). Bench press strength increased to a greater extent for WC compared to W and P (p < .05). Knee extension peak torque increased with training for WC and W (p < .05), but not for P. All other measures increased to a similar extent across groups. Continued training without supplementation for an additional 6 weeks resulted in maintenance of strength and lean tissue mass in all groups. Males that supplemented with whey protein while resistance training demonstrated greater improvement in knee extension peak torque and lean tissue mass than males engaged in training alone. Males that supplemented with a combination of whey protein and creatine had greater increases in lean tissue mass and bench press than those who supplemented with only whey protein or placebo. However, not all strength measures were improved with supplementation, since subjects who supplemented with creatine and/or whey protein had similar increases in squat strength and knee flexion peak torque compared to subjects who received placebo.
The purpose of this study was to investigate the effects of creatine (Cr) supplementation on force generation during an isometric bench-press in resistance-trained men.
32 resistance-trained men were matched for peak isometric force and assigned in double-blind fashion to either a Cr or placebo group. Subjects performed an isometric bench-press test involving five maximal isometric contractions before and after 5 d of Cr (20 g.d-1 Cr + 180 g.d-1 dextrose) or placebo (200 g.d-1 dextrose). Body composition was measured before and after supplementation. Subjects completed 24-h urine collections throughout the study period; these were subsequently analyzed to provide total Cr and creatinine excretion.
The amount of Cr retained over the supplementation period was 45 +/- 18 g (mean +/- SD), with an estimated intramuscular Cr storage of 43 (13-61) mmol x kg(-1) x dry weight muscle (median [range]). Four subjects in the Cr group were classified as “nonresponders” (< or =21 mmol x kg(-1) x dry weight muscle increase following Cr supplementation) and the remaining 17 subjects were classed as “responders” (> or =32 mmol x kg(-1) x dry weight muscle). For the Cr group, peak force and total force pre- or post-supplementation were not different from placebo. However, when the analysis was confined to the responders, both the change in peak force [Repetition 2: 59(81) N vs -26(85) N; Repetition 3: 45(59) N vs -26(64) N) and the change in total force (Repetition 1: 1471(1274) N vs 209(1517) N; Repetition 2: 1575(1254) N vs 196(1413) N; Repetition 3: 1278(1245) N vs -3(1118) N; Repetition 4: 918(935) N vs -83(1095) N] post-supplementation were significantly greater compared with the placebo group (P < 0.01). For the Cr group, estimated Cr uptake was inversely correlated with training status (r = -0.68, N = 21, P = 0.001). Cr significantly increased body weight (84.1 +/- 8.6 kg pre- vs 85.3 +/- 8.3 kg post-supplementation) and fat-free mass (71.8 +/- 6.0 kg pre- vs 72.6 +/- 6.0 kg post-supplementation), with the magnitude of increase being significantly greater in the responder group than in the placebo group.
Five days of Cr supplementation increased body weight and fat-free body mass in resistance-trained men who were classified as responders. Peak force and total force during a repeated maximal isometric bench-press test were also significantly greater in the responders compared to the placebo group.
The purpose of this investigation was to examine the effects of 6 wk of oral creatine supplementation during a periodized program of arm flexor strength training on arm flexor IRM, upper arm muscle area, and body composition.
Twenty-three male volunteers with at least 1 yr of weight training experience were assigned in a double blind fashion to two groups (Cr, N = 10; Placebo, N = 13) with no significant mean pretest one repetition maximum (IRM) differences in arm flexor strength. Cr ingested 5 g of creatine monohydrate in a flavored, sucrose drink four times per day for 5 d. After 5 d, supplementation was reduced to 2 g x d(-1). Placebo ingested a flavored, sucrose drink. Both drinks were 500 mL and made with 32 g of sucrose. IRM strength of the arm flexors, body composition, and anthropometric upper arm muscle area (UAMA) were measured before and after a 6-wk resistance training program. Subjects trained twice per week with training loads that began at 6RM and progressed to 2RM.
IRM for Cr increased (P < 0.01) from (mean +/- SD) 42.8 +/- 17.7 kg to 54.7 +/- 14.1 kg, while IRM for Placebo increased (P < 0.01) from 42.5 +/- 15.9 kg to 49.3 +/- 15.7 kg. At post-test IRM was significantly (P < 0.01) greater for Cr than for Placebo. Body mass for Cr increased (P < 0.01) from 86.7 +/- 14.7 kg to 88.7 +/- 13.8 kg. Fat-free mass for Cr increased (P < 0.01) from 71.2 +/- 10.0 kg to 72.8 +/- 10.1 kg. No changes in body mass or fat-free mass were found for Placebo. There were no changes in fat mass and percent body fat for either group. UAMA increased (P < 0.01) 7.9 cm2 for Cr and did not change for Placebo.
Creatine supplementation during arm flexor strength training lead to greater increases in arm flexor muscular strength, upper arm muscle area, and fat-free mass than strength training alone
To determine the effects of creatine (Cr) supplementation (20 g x d(-1) during 5 d) on maximal strength, muscle power production during repetitive high-power-output exercise bouts (MRPB), repeated running sprints, and endurance in handball players.
Nineteen trained male handball players were randomly assigned in a double-blind fashion to either creatine (N = 9) or placebo (N = 10) group. Before and after supplementation, subjects performed one-repetition maximum half-squat (1RM(HS) and bench press (1RM(BP)), 2 sets of MRPB consisting of one set of 10 continuous repetitions (R10) followed by 1 set until exhaustion (R(max)), with exactly 2-min rest periods between each set, during bench-press and half-squat protocols with a resistance equal to 60 and 70% of the subjects’ 1RM, respectively. In addition, a countermovement jumping test (CMJ) interspersed before and after the MRPB half-squat exercise bouts and a repeated sprint running test and a maximal multistage discontinuous incremental running test (MDRT) were performed.
Cr supplementation significantly increased body mass (from 79.4 +/- 8 to 80 +/- 8 kg; P < 0.05), number of repetitions performed to fatigue, and total average power output values in the R(max) set of MRPB during bench press (21% and 17%, respectively) and half-squat (33% and 20%, respectively), the 1RM(HS) (11%), as well as the CMJ values after the MRPB half-squat (5%), and the average running times during the first 5 m of the six repeated 15-m sprints (3%). No changes were observed in the strength, running velocity, or body mass measures in the placebo group during the experimental period.
Short-term Cr supplementation leads to significant improvements in lower-body maximal strength, maximal repetitive upper- and lower-body high-power exercise bouts, and total repetitions performed to fatigue in the R(max) set of MRPB, as well as enhanced repeated sprint performance and attenuated decline in jumping ability after MRPB in highly trained handball players. Cr supplementation did not result in any improvement in upper-body maximal strength and in endurance running performance.
To determine the effects of creatine supplementation during short-term resistance training overreaching on performance, body composition, and resting hormone concentrations, 17 men were randomly assigned to supplement with 0.3 g/kg per day of creatine monohydrate (CrM: n=9) or placebo (P: n=8) while performing resistance exercise (5 days/week for 4 weeks) followed by a 2-week taper phase. Maximal squat and bench press and explosive power in the bench press were reduced during the initial weeks of training in P but not CrM. Explosive power in the bench press, body mass, and lean body mass (LBM) in the legs were augmented to a greater extent in CrM ( P<or=0.05) by the end of the 6-week period. A tendency for greater 1-RM squat improvement ( P=0.09) was also observed in CrM. Total testosterone (TT) and the free androgen index (TT/SHBG) decreased in CrM and P, reaching a nadir at week 3, whereas sex hormone binding globulin (SHBG) responded in an opposite direction. Cortisol significantly increased after week 1 in CrM (+29%), and returned to baseline at week 2. Insulin was significantly depressed at week 1 (-24%) and drifted back toward baseline during weeks 2-4. Growth hormone and IGF-I levels were not affected. Therefore, some measures of muscular performance and body composition are enhanced to a greater extent following the rebound phase of short-term resistance training overreaching with creatine supplementation and these changes are not related to changes in circulating hormone concentrations obtained in the resting, postabsorptive state. In addition, creatine supplementation appears to be effective for maintaining muscular performance during the initial phase of high-volume resistance training overreaching that otherwise results in small performance decrements.
Chronic supplementation with creatine monohydrate has been shown to promote increases in total intramuscular creatine, phosphocreatine, skeletal muscle mass, lean body mass and muscle fiber size. Furthermore, there is robust evidence that muscular strength and power will also increase after supplementing with creatine. However, it is not known if the timing of creatine supplementation will affect the adaptive response to exercise. Thus, the purpose of this investigation was to determine the difference between pre versus post exercise supplementation ofcreatine on measures of body composition and strength.
Nineteen healthy recreational male bodybuilders (mean ± SD; age: 23.1 ± 2.9; height: 166.0 ± 23.2 cm; weight: 80.18 ± 10.43 kg) participated in this study. Subjects were randomly assigned to one of the following groups: PRE-SUPP or POST-SUPP workout supplementation ofcreatine (5 grams). The PRE-SUPP group consumed 5 grams of creatine immediately before exercise. On the other hand, the POST-SUPP group consumed 5 grams immediately after exercise. Subjects trained on average five days per week for four weeks. Subjects consumed the supplement on the two non-training days at their convenience. Subjects performed a periodized, split-routine, bodybuilding workout five days per week (Chest-shoulders-triceps; Back-biceps, Legs, etc.). Body composition (Bod Pod®) and 1-RM bench press (BP) were determined. Diet logs were collected and analyzed (one random day per week; four total days analyzed).
2×2 ANOVA results – There was a significant time effect for fat-free mass (FFM) (F = 19.9; p = 0.001) and BP (F = 18.9; p < 0.001), however, fat mass (FM) and body weight did not reach significance. While there were trends, no significant interactions were found. However, using magnitude-based inference, supplementation with creatine post workout is possibly more beneficial in comparison to pre workout supplementationwith regards to FFM, FM and 1-RM BP. The mean change in the PRE-SUPP and POST-SUPP groups for body weight (BW kg), FFM (kg), FM (kg) and 1-RM bench press (kg) were as follows, respectively: Mean ± SD; BW: 0.4 ± 2.2 vs. 0.8 ± 0.9; FFM: 0.9 ± 1.8 vs. 2.0 ± 1.2; FM: -0.1 ± 2.0 vs. -1.2 ± 1.6; Bench Press 1-RM: 6.6 ± 8.2 vs. 7.6 ± 6.1. Qualitative inference represents the likelihood that the true value will have the observed magnitude. Furthermore, there were no differences in caloric or macronutrient intake between the groups.
Creatine supplementation plus resistance exercise increases fat-free mass and strength. Based on the magnitude inferences it appears that consuming creatine immediately post-workout is superior to pre-workout vis a vis body composition and strength.
Studies involving chronic creatine supplementation in elite soccer players are scarce. Therefore, the aim of this study was to examine the effects of creatine monohydrate supplementation on lower-limb muscle power in Brazilian elite soccer players (n = 14 males) during pre-season training.
This was a randomized, double-blind, placebo-controlled parallel-group study. Brazilian professional elite soccer players participated in this study. During the pre-season (7 weeks), all the subjects underwent a standardized physical and specific soccer training. Prior to and after either creatine monohydrate or placebo supplementation, the lower-limb muscle power was measured by countermovement jump performance. The Jumping performance was compared between groups at baseline (p = 0.99). After the intervention, jumping performance was lower in the placebo group (percent change = - 0.7%; ES = - 0.3) than in the creatine group (percent change = + 2.4%; ES = + 0.1), but it did not reach statistical significance (p = 0.23 for time x group interaction). Fisher’s exact test revealed that the proportion of subjects that experienced a reduction in jumping performance was significantly greater in the placebo group than in the creatine group (5 and 1, respectively; p = 0.05) after the training. The magnitude-based inferences demonstrated that placebo resulted in a possible negative effect (50%) in jumping performance, whereas creatine supplementation led to a very likely trivial effect (96%) in jumping performance in the creatine group.
Creatine monohydrate supplementation prevented the decrement in lower-limb muscle power in elite soccer players during a pre-season progressive training.
To investigate the effect of creatine (CR) supplementation on the acute interference induced by aerobic exercise on subsequent maximum dynamic strength (1RM) and strength endurance (SE, total number of repetitions) performance.
Thirty-two recreationally strength-trained men were submitted to a graded exercise test to determine maximal oxygen consumption (VO2max: 41.56 ± 5.24 ml kg(-1) min(-1)), anaerobic threshold velocity (ATv: 8.3 ± 1.18 km h(-1)), and baseline performance (control) on the 1RM and SE (4 × 80 % 1RM to failure) tests. After the control tests, participants were randomly assigned to either a CR (20 g day(-1) for 7 days followed by 5 g day(-1) throughout the study) or a placebo (PL-dextrose) group, and then completed 4 experimental sessions, consisting of a 5-km run on a treadmill either continuously (90 % ATv) or intermittently (1:1 min at vVO2max) followed by either a leg- or bench-press SE/1RM test.
CR was able to maintain the leg-press SE performance after the intermittent aerobic exercise when compared with C (p > 0.05). On the other hand, the PL group showed a significant decrease in leg-press SE (p ≤ 0.05). CR supplementation significantly increased bench-press SE after both aerobic exercise modes, while the bench-press SE was not affected by either mode of aerobic exercise in the PL group. Although small increases in 1RM were observed after either continuous (bench press and leg press) or intermittent (bench press) aerobic exercise in the CR group, they were within the range of variability of the measurement. The PL group only maintained their 1RM.
In conclusion, the acute interference effect on strength performance observed in concurrent exercise may be counteracted by CRsupplementation.
To determine the effects of 28 d of creatine supplementation during training on body composition, strength, sprint performance, and hematological profiles.
In a double-blind and randomized manner, 25 NCAA division IA football players were matched-paired and assigned to supplement their diet for 28 d during resistance/agility training (8 h x wk[-1]) with a Phosphagen HP (Experimental and Applied Sciences, Golden, CO) placebo (P) containing 99 g x d(-1) of glucose, 3 g x d(-1) of taurine, 1.1 g x d(-1) of disodium phosphate, and 1.2 g x d(-1) of potassium phosphate (P) or Phosphagen HP containing the P with 15.75 g x d(-1) of HPCE pure creatine monohydrate (HP). Before and after supplementation, fasting blood samples were obtained; total body weight, total body water, and body composition were determined; subjects performed a maximal repetition test on the isotonic bench press, squat, and power clean; and subjects performed a cycle ergometer sprint test (12 x 6-s sprints with 30-s rest recovery).
Hematological parameters remained within normal clinical limits for active individuals with no side effects reported. Total body weight significantly increased (P < 0.05) in the HP group (P 0.85 +/- 2.2; HP 2.42 +/- 1.4 kg) while no differences were observed in the percentage of total body water. DEXA scanned body mass (P 0.77 +/- 1.8; HP 2.22 +/- 1.5 kg) and fat/bone-free mass (P 1.33 +/- 1.1; HP 2.43 +/- 1.4 kg) were significantly increased in the HP group. Gains in bench press lifting volume (P -5 +/- 134; HP 225 +/- 246 kg), the sum of bench press, squat, and power clean lifting volume (P 1,105 +/- 429; HP 1,558 +/- 645 kg), and total work performed during the first five 6-s sprints was significantly greater in the HP group.
The addition of creatine to the glucose/taurine/electrolyte supplement promoted greater gains in fat/bone-free mass, isotonic lifting volume, and sprint performance during intense resistance/agility training.
Creatine monohydrate (Cr), the most diffuse supplement in the sports industry, is receiving greater attention because of its beneficial effects in a wide number of human degenerative diseases and conditions. These effects can be barely explained on the basis of the sole ergogenic role of the Cr/CrP system. Indeed, a wide number of research articles indicate that Cr is capable of exerting multiple, non-energy related, effects on diverse and relevant cellular targets. Among these effects, the antioxidant activity of Cr emerges as an additional mechanism which is likely to play a supportive role in the Cr-cytoprotection paradigm.
Creatine is the most popular supplement proposed to be an ergogenic aid. There is some evidence in the literature that creatine supplementationincreases lean body mass, muscular strength, and sprint power. However, the efficacy of creatine has not been consistent, and the potential mechanisms are unresolved. While limited evidence that suggests that creatine could possess an antioxidant effect this has not been tested directly. Because oxidants such as free radicals can affect muscle fatigue and protein turnover, it is important to know whether creatine can neutralize free radicals and other reactive oxygen species. We tested the hypothesis that creatine would remove superoxide anions (O(*-)(2)), peroxynitrite (OONO-), hydrogen peroxide, and lipid peroxides (t-butyl hydroperoxide). We also determined whether creatine displayed a significant antioxidant scavenging capacity (ASC) using 2,2′-azino-bis(3-ethylbenzothiazolamine-6-sulfonic acid) (ABTS+) quenching as a marker. Creatine did not significantly reduce levels of hydrogen peroxide or lipid peroxidation. In contrast, creatine displayed a significant ability to remove ABTS+, O(*-)(2), and OONO- when compared with controls. Creatine quenching of ABTS+ was less than physiological levels of reduced glutathione (0.375 mM). To our knowledge, this is the first evidence that creatine has the potential to act as a direct antioxidant against aqueous radical and reactive species ions.
Creatine is a key intermediate in energy metabolism and supplementation of creatine has been used for increasing muscle mass, strength and endurance. Creatine supplementation has also been reported to trigger the skeletal muscle expression of insulin like growth factor I, to increase the fat-free mass and improve cognition in elderly, and more explorative approaches like transcriptomics has revealed additional information. The aim of the present study was to reveal additional insight into the biochemical effects of creatine supplementation at the protein and metabolite level by integrating the explorative techniques, proteomics and NMR metabonomics, in a systems biology approach.
Differentiated mouse myotube cultures (C2C12) were exposed to 5 mM creatine monohydrate (CMH) for 24 hours. For proteomics studies, lysed myotubes were analyzed in single 2-DGE gels where the first dimension of protein separation was pI 5-8 and second dimension was a 12.5% Criterion gel. Differentially expressed protein spots of significance were excised from the gel, desalted and identified by peptide mass fingerprinting using MALDI-TOF MS. For NMR metabonomic studies, chloroform/methanol extractions of the myotubes were subjected to one-dimensional 1H NMR spectroscopy and the intracellular oxidative status of myotubes was assessed by intracellular DCFH2 oxidation after 24 h pre-incubation with CMH.
The identified differentially expressed proteins included vimentin, malate dehydrogenase, peroxiredoxin, thioredoxin dependent peroxide reductase, and 75 kDa and 78 kDa glucose regulated protein precursors. After CMH exposure, up-regulated proteomic spots correlated positively with the NMR signals from creatine, while down-regulated proteomic spots were negatively correlated with these NMR signals. The identified differentially regulated proteins were related to energy metabolism, glucose regulated stress, cellular structure and the antioxidative defence system. The suggested improvement of the antioxidative defence was confirmed by a reduced intracellular DCFH2 oxidation with increasing concentrations of CMH in the 24 h pre-incubation medium.
The explorative approach of this study combined with the determination of a decreased intracellular DCFH2 oxidation revealed an additional stimulation of cellular antioxidative mechanisms when myotubes were exposed to CMH. This may contribute to an increased exercise performance mediated by increased ability to cope with training-induced increases in oxidative stress.
Recent findings have indicated that creatine supplementation may affect glucose metabolism. This study aimed to examine the effects of creatine supplementation, combined with aerobic training, on glucose tolerance in sedentary healthy male. Subjects (n = 22) were randomly divided in two groups and were allocated to receive treatment with either creatine (CT) ( approximately 10 g . day over three months) or placebo (PT) (dextrose). Administration of treatments was double blind. Both groups underwent moderate aerobic training. An oral glucose tolerance test (OGTT) was performed and both fasting plasma insulin and the homeostasis model assessment (HOMA) index were assessed at the start, and after four, eight and twelve weeks. CT demonstrated significant decrease in OGTT area under the curve compared to PT (P = 0.034). There were no differences between groups or over time in fasting insulin or HOMA. The results suggest that creatine supplementation, combined with aerobic training, can improve glucose tolerance but does not affect insulin sensitivity, and may warrant further investigation with diabetic subjects.
Supplemental creatine has been promoted for its positive health effects and is best known for its use by athletes to increase muscle mass. In addition to its role in physical performance, creatine supplementation has protective effects on the brain in models of neuronal damage and also alters mood state and cognitive performance. Creatine is found in high protein foods, such as fish or meat, and is also produced endogenously from the biosynthesis of arginine, glycine, and methionine. Changes in brain creatine levels, as measured using magnetic resonance spectroscopy, are seen in individuals exposed to drugs of abuse and depressed individuals. These changes in brain creatine indicate that energy metabolism differs in these populations relative to healthy individuals. Recent work shows that creatine supplementation has the ability to function in a manner similar to antidepressant drugs and can offset negative consequences of stress. These observations are important in relation to addictive behaviors as addiction is influenced by psychological factors such as psychosocial stress and depression. The significance of altered brain levels of creatine in drug-exposed individuals and the role of creatine supplementation in models of drug abuse have yet to be explored and represent gaps in the current understanding of brain energetics and addiction.
Athletes, body builders, and military personnel use dietary creatine as an ergogenic aid to boost physical performance in sports involving short bursts of high-intensity muscle activity. Lesser known is the essential role creatine, a natural regulator of energy homeostasis, plays in brain function and development. Creatine supplementation has shown promise as a safe, effective, and tolerable adjunct to medication for the treatment of brain-related disorders linked with dysfunctional energy metabolism, such as Huntington’s Disease and Parkinson’s Disease. Impairments in creatine metabolism have also been implicated in the pathogenesis of psychiatric disorders, leaving clinicians, researchers and patients alike wondering if dietary creatinehas therapeutic value for treating mental illness. The present review summarizes the neurobiology of the creatine-phosphocreatine circuit and its relation to psychological stress, schizophrenia, mood and anxiety disorders. While present knowledge of the role of creatine in cognitive and emotional processing is in its infancy, further research on this endogenous metabolite has the potential to advance our understanding of the biological bases of psychopathology and improve current therapeutic strategies.
There is a substantial body of literature, which has demonstrated that creatine has neuroprotective effects both in vitro and in vivo. Creatine can protect against excitotoxicity as well as against β-amyloid toxicity in vitro. We carried out studies examining the efficacy of creatine as a neuroprotective agent in vivo. We demonstrated that creatine can protect against excitotoxic lesions produced by N-methyl-D: -aspartate. We also showed that creatine is neuroprotective against lesions produced by the toxins malonate and 3-nitropropionic acid (3-NP) which are reversible and irreversible inhibitors of succinate dehydrogenase, respectively. Creatine produced dose-dependent neuroprotective effects against MPTP toxicity reducing the loss of dopamine within the striatum and the loss of dopaminergic neurons in the substantia nigra. We carried out a number of studies of the neuroprotective effects of creatine in transgenic mouse models of neurodegenerative diseases. We demonstrated that creatine produced an extension of survival, improved motor performance, and a reduction in loss of motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). Creatine produced an extension of survival, as well as improved motor function, and a reduction in striatal atrophy in the R6/2 and the N-171-82Q transgenic mouse models of Huntington’s disease (HD), even when its administration was delayed until the onset of disease symptoms. We recently examined the neuroprotective effects of a combination of coenzyme Q10 (CoQ10) with creatine against both MPTP and 3-NP toxicity. We found that the combination of CoQ and creatine together produced additive neuroprotective effects in a chronic MPTP model, and it blocked the development of alpha-synuclein aggregates. In the 3-NP model of HD, CoQ and creatine produced additive neuroprotective effects against the size of the striatal lesions. In the R6/2 transgenic mouse model of HD, the combination of CoQ and creatine produced additive effects on improving survival. Creatine may stabilize mitochondrial creatine kinase, and prevent activation of the mitochondrial permeability transition. Creatine, however, was still neuroprotective in mice, which were deficient in mitochondrial creatine kinase. Administration of creatine increases the brain levels of creatine and phosphocreatine. Due to its neuroprotective effects, creatine is now in clinical trials for the treatment of Parkinson’s disease (PD) and HD. A phase 2 futility trial in PD showed approximately a 50% improvement in Unified Parkinson’s Disease Rating Scale at one year, and the compound was judged to be non futile. Creatine is now in a phase III clinical trial being carried out by the NET PD consortium. Creatine reduced plasma levels of 8-hydroxy-2-deoxyguanosine in HD patients phase II trial and was well-tolerated. Creatine is now being studied in a phase III clinical trial in HD, the CREST trial. Creatine, therefore, shows great promise in the treatment of a variety of neurodegenerative diseases.
Significant progress has been made in identifying neuroprotective agents and their translation to patients with neurological disorders. While the direct causative pathways of neurodegeneration remain unclear, they are under great clinical and experimental investigation. There are a number of interrelated pathogenic mechanisms triggering molecular events that lead to neuronal death. One putative mechanism reported to play a prominent role in the pathogenesis of neurological diseases is impaired energy metabolism. If reduced energy stores play a role in neuronal loss, then therapeutic strategies that buffer intracellular energy levels may prevent or impede the neurodegenerative process. Recent studies suggest that impaired energy production promotes neurological disease onset and progression. Sustained ATP levels are critical to cellular homeostasis and may have both direct and indirect influence on pathogenic mechanisms associated with neurological disorders. Creatine is a critical component in maintaining cellular energy homeostasis, and its administration has been reported to be neuroprotective in a wide number of both acute and chronic experimental models of neurological disease. In the context of this chapter, we will review the experimental evidence for creatine supplementation as a neurotherapeutic strategy in patients with neurological disorders, including Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease, as well as in ischemic stroke, brain and spinal cord trauma, and epilepsy.
Substantial evidence indicates bioenergetic dysfunction and mitochondrial impairment contribute either directly and/or indirectly to the pathogenesis of numerous neurodegenerative disorders. Treatment paradigms aimed at ameliorating this cellular energy deficit and/or improving mitochondrial function in these neurodegenerative disorders may prove to be useful as a therapeutic intervention. Creatine is a molecule that is produced both endogenously, and acquired exogenously through diet, and is an extremely important molecule that participates in buffering intracellular energy stores. Once creatine is transported into cells, creatine kinase catalyzes the reversible transphosphorylation of creatine via ATP to enhance the phosphocreatine energy pool. Creatine kinase enzymes are located at strategic intracellular sites to couple areas of high energy expenditure to the efficient regeneration of ATP. Thus, the creatine kinase/phosphocreatine system plays an integral role in energy buffering and overall cellular bioenergetics. Originally, exogenous creatine supplementation was widely used only as an ergogenic aid to increase the phosphocreatine pool within muscle to bolster athletic performance. However, the potential therapeutic value of creatine supplementation has recently been investigated with respect to various neurodegenerative disorders that have been associated with bioenergetic deficits as playing a role in disease etiology and/or progression which include; Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), and Huntington’s disease. This review discusses the contribution of mitochondria and bioenergetics to the progression of these neurodegenerative diseases and investigates the potential neuroprotective value of creatine supplementation in each of these neurological diseases. In summary, current literature suggests that exogenous creatine supplementation is most efficacious as a treatment paradigm in Huntington’s and Parkinson’s disease but appears to be less effective for ALS and Alzheimer’s disease.
Creatine (Cr) plays a central role in energy provision through a reaction catalyzed by phosphorylcreatine kinase. Furthermore, this amine enhances both gene expression and satellite cell activation involved in hypertrophic response. Recent findings have indicated that Cr supplementation has a therapeutic role in several diseases characterized by atrophic conditions, weakness, and metabolic disturbances (i.e., in the muscle, bone, lung, and brain). Accordingly, there has been an evidence indicating that Cr supplementation is capable of attenuating the degenerative state in some muscle disorders (i.e., Duchenne and inflammatory myopathies), central nervous diseases (i.e., Parkinson’s, Huntington’s, and Alzheimer’s), and bone and metabolic disturbances (i.e., osteoporosis and type II diabetes). In light of this, Cr supplementation could be used as a therapeutic tool for the elderly. The aim of this review is to summarize the main studies conducted in this field and to highlight the scientific and clinical perspectives of this promising therapeutic supplement.
Recently, it was shown that glycogen supercompensation tended (P = 0.06) to be greater if creatine and glycogen were loaded simultaneously. Because the authors suggested that creatine loading increased cell volumes and, therefore, enhanced glycogen supercompensation, we decided to determine whether an enhanced glycogen supercompensation could be realized if the glycogen loading protocol was preceded by a 5-d creatine load.
Twelve men (19-28 yr) performed two standard glycogen loading protocols interspersed with a standard creatine load of 20 g.d(-1) for 5 d. The vastus lateralis muscle was biopsied before and after each loading protocol.
The initial glycogen loading protocol showed a significant 4% increase (P < 0.05) in muscle glycogen (Delta upward arrow 164 +/- 87 mmol.kg(-1) d.m.), and no change (P > 0.05) in total muscle creatine. Biopsies pre- and post-creatine loading showed significant increases in total muscle creatine levels in both the left leg (Delta upward arrow 41.1 +/- 31.1 mmol.kg(-1) d.m.) and the right leg (Delta upward arrow 36.6 +/- 19.8 mmol.kg(-1) d.m.), with no change in either leg’s muscle glycogen content. After the final glycogen loading, a significant 53% increase in muscle glycogen (Delta upward arrow 241 +/- 150 mmol.kg-1 d.m.) was detected. Finally, the postcreatine load total glycogen content (694 +/- 156 mmol.kg(-1) d.m.) was significantly (P < 0.05) greater than the precreatine load total glycogen content (597 +/- 142 mmol.kg(-1) d.m.).
It is suggested that a muscle’s glycogen loading capacity is influenced by its initial levels of creatine and the accompanying alterations in cell volume.
This study determined the effects of 28 days of oral creatine ingestion (days 1 to 5 = 20g/d; [5 g 4 times daily]: days 6 to 28 = 10 g/d; [5 g twice daily]) alone and with resistance training (5 hours/week) on resting metabolic rate (RMR), body composition, muscular strength (1RM), and limb blood flow (LBF). Using a double-blind, placebo-controlled design, 30 healthy male volunteers (21 +/- 3 years; 18 to 30 years) were randomly assigned to 1 of 3 groups; pure creatine monohydrate alone (Cr; n = 10), creatine plus resistance training (Cr-RT; n = 10), or placebo plus resistance training (P-RT; n = 10). Body composition (DEXA, Lunar DPX-IQ), body mass, bench, and leg press 1RM (isotonic), RMR (indirect calorimetry; ventilated hood), and forearm and calf LBF (venous occlusive plethysmography) were obtained on all 30 subjects on 3 occasions beginning at approximately 6:00 AM following an overnight fast and 24 hours removed from the last training session; baseline (day 0), and 7 days and 29 days following the interventions. No differences existed among groups at baseline for any of the variables measured. Following the 28-day interventions, body mass (Cr, 73.9 +/- 11.5 v 75.6 +/- 12.5 kg; Cr-RT, 78.8 +/- 6.7 v 80.8 +/- 6.8 kg; P <.01) and total body water (Cr, 40.4 +/- 6.8 v 42.6 +/- 7.2 L, 5.5%; Cr-RT, 40.6 +/- 2.4 v 42.3 +/- 2.2 L, 4.3%; P <.01) increased significantly in Cr and Cr-RT, but remained unchanged in P-RT, whereas, fat-free mass (FFM) increased significantly in Cr-RT (63 +/- 2.8 v 64.7 +/- 3.6 kg; P <.01) and showed a tendency to increase in Cr (58.1 +/- 8.1 v 59 +/- 8.8 kg; P =.07). Following the 28-day period, all groups significantly increased (P <.01) bench (Cr, 77.3 +/- 4 v 83.2 +/- 3.6 kg; Cr-RT, 76.8 +/- 4.5 v 90.5 +/- 4.5 kg; P-RT, 76.0 +/- 3.4 v 85.5 +/- 3.2 kg), and leg press (Cr, 205.5 +/- 14.5 v 238.6 +/- 13.2 kg; Cr-RT, 167.7 +/- 13.2 v 238.6 +/- 17.3 kg; P-RT, 200.5 +/- 9.5 v 255 +/- 13.2 kg) 1RM muscular strength. However, Cr-RT improved significantly more (P <.05) on the leg press 1RM than Cr and P-RT and the bench press 1RM than Cr (P <.01). Calf (30%) and forearm (38%) LBF increased significantly (P <.05) in the Cr-RT, but remained unchanged in the Cr and P-RT groups following the supplementation period. RMR expressed on an absolute basis was increased in the Cr (1,860.1 +/- 164.9 v 1,907 +/- 173.4 kcal/d, 2.5%; P <.05) and Cr-RT (1,971.4 +/- 171.8 v 2,085.7 +/- 183.6 kcal/d, 5%; P <.05), but remained unchanged from baseline in P-RT. Total cholesterol decreased significantly in Cr-RT (-9.9%; 172 +/- 27 v 155 +/- 26 mg/dL; P <.01) compared with Cr (174 +/- 46 v 178 +/- 43 mg/dL) and P-RT (162 +/- 32 v 161 +/- 36 mg/dL) following the 28-day intervention. These findings suggest that the addition of creatine supplementation to resistance training significantly increases total and fat-free body mass, muscular strength, peripheral blood flow, and resting energy expenditure and improves blood cholesterol.
Nutritional status influences muscle growth and athletic performance, but little is known about the effect of nutritional supplements, such as creatine, on satellite cell mitotic activity. The purpose of this study was to examine the effect of oral creatine supplementation on muscle growth, compensatory hypertrophy, and satellite cell mitotic activity. Compensatory hypertrophy was induced in the rat plantaris muscle by removing the soleus and gastrocnemius muscles. Immediately following surgery, a group of six rats was provided with elevated levels of creatine monohydrate in their diet. Another group of six rats was maintained as a non-supplemented control group. Twelve days following surgery, all rats were implanted with mini-osmotic pumps containing the thymidine analog 5-bromo-2′-deoxyuridine (BrdU) to label mitotically active satellite cells. Four weeks after the initial surgery the rats were killed, plantaris muscles were removed and weighed. Subsequently, BrdU-labeled and non-BrdU-labeled nuclei were identified on enzymatically isolated myofiber segments. Muscle mass and myofiber diameters were larger (P < 0.05) in the muscles that underwent compensatory hypertrophy compared to the control muscles, but there were no differences between muscles from creatine-supplemented and non-creatine-supplemented rats. Similarly, compensatory hypertrophy resulted in an increased (P < 0.05) number of BrdU-labeled myofiber nuclei, but creatine supplementation in combination with compensatory hypertrophy resulted in a higher (P < 0.05) number of BrdU-labeled myofiber nuclei compared to compensatory hypertrophy without creatine supplementation. Thus, creatine supplementation in combination with an increased functional load results in increased satellite cell mitotic activity.
A series of studies were conducted in which compounds commonly shown to be ergogenic aids for strength athletes if taken orally were evaluated for their ability to directly induce postnatal muscle stem cell proliferation or differentiation/fusion in vitro.
Compounds tested were creatine monohydrate, creatine pyruvate, L-glutamine, dehydroepiandrosterone (DHEA), androstenedione, Ma Huang (Ephedra sinensis) extract, and Zhi Shi (Citrus aurantium) extract. Dulbecco’s modified eagle medium, supplemented with minimal levels of serum and antibiotics, was used as the initial vehicle for the test compounds. Subsequently, a defined treatment medium termed ITTC was used. Satellite cells were exposed to the test compounds for the indicated times and then evaluated by counting mononucleated and multinucleated (fused) cells.
In serum-containing media, none of the treatment groups displayed increased proliferation over that of the control. However, in the differentiation cultures, 0.10% creatine monohydrate increased differentiation over that of the control cultures. When 0.10% creatine monohydrate was added to defined media formulations, all treatments but one demonstrated increased differentiation over the 0.5% serum control. Time course experiments, which followed the effect of 0.10% creatine monohydrate contained in ITTC defined media over 120 h, suggested that cells exposed to this treatment differentiated earlier and to a greater level than cells exposed to ITTC alone.
Creatine in the monohydrate form induced differentiation of myogenic satellite cells. Other agents examined did not increase satellite cell proliferation or differentiation. These results provide initial evidence for a mechanistic understanding of observed effects in vivo of increased muscular size and strength from creatine supplementation.
The present study investigated the influence of creatine and protein supplementation on satellite cell frequency and number of myonuclei in human skeletal muscle during 16 weeks of heavy-resistance training. In a double-blinded design 32 healthy, male subjects (19-26 years) were assigned to strength training (STR) while receiving a timed intake of creatine (STR-CRE) (n=9), protein (STR-PRO) (n=8) or placebo (STR-CON) (n=8), or serving as a non-training control group (CON) (n=7). Supplementation was given daily (STR-CRE: 6-24 g creatine monohydrate, STR-PRO: 20 g protein, STR-CON: placebo). Furthermore, timed protein/placebo intake were administered at all training sessions. Muscle biopsies were obtained at week 0, 4, 8 (week 8 not CON) and 16 of resistance training (3 days per week). Satellite cells were identified by immunohistochemistry. Muscle mean fibre (MFA) area was determined after histochemical analysis. All training regimes were found to increase the proportion of satellite cells, but significantly greater enhancements were observed with creatine supplementation at week 4 (compared to STR-CON) and at week 8 (compared to STR-PRO and STR-CON) (P<0.01-0.05). At week 16, satellite cell number was no longer elevated in STR-CRE, while it remained elevated in STR-PRO and STR-CON. Furthermore, creatine supplementation resulted in an increased number of myonuclei per fibre and increases of 14-17% in MFA at week 4, 8 and 16 (P<0.01). In contrast, STR-PRO showed increase in MFA only in the later (16 week, +8%) and STR-CON only in the early (week 4, +14%) phases of training, respectively (P<0.05). In STR-CRE a positive relationship was found between the percentage increases in MFA and myonuclei from baseline to week 16, respectively (r=0.67, P<0.05). No changes were observed in the control group (CON). In conclusion, the present study demonstrates for the first time that creatine supplementation in combination with strength training amplifies the training-induced increase in satellite cell number and myonuclei concentration in human skeletal muscle fibres, thereby allowing an enhanced muscle fibre growth in response to strength training.
Myoblast fusion is essential for muscle development, postnatal growth and muscle repair after injury. Recent studies have demonstrated roles for actin polymerization during myoblast fusion. Dynamic cytoskeletal assemblies directing cell-cell contact, membrane coalescence and ultimately fusion require substantial cellular energy demands. Various energy generating systems exist in cells but the partitioning of energy sources during myoblast fusion is unknown. Here, we demonstrate a novel role for phosphocreatine (PCr) as a spatiotemporal energy buffer during primary mouse myoblast fusion with nascent myotubes. Creatine treatment enhanced cell fusion in a creatine kinase (CK)-dependent manner suggesting that ATP-consuming reactions are replenished through the PCr/CK system. Furthermore, selective inhibition of actin polymerization prevented myonuclear addition following creatine treatment. As myotube formation is dependent on cytoskeletal reorganization, our findings suggest that PCr hydrolysis is coupled to actin dynamics during myoblast fusion. We conclude that myoblast fusion is a high-energy process, and can be enhanced by PCr buffering of energy demands during actin cytoskeletal rearrangements in myoblast fusion. These findings implicate roles for PCr as a high-energy phosphate buffer in the fusion of multiple cell types including sperm/oocyte, trophoblasts and macrophages. Furthermore, our results suggest the observed beneficial effects of oral creatine supplementation in humans may result in part from enhanced myoblast fusion.
A broad spectrum of beneficial effects has been ascribed to creatine (Cr), phosphocreatine (PCr) and their cyclic analogues cyclo-(cCr) and phospho-cyclocreatine (PcCr). Cr is widely used as nutritional supplement in sports and increasingly also as adjuvant treatment for pathologies such as myopathies and a plethora of neurodegenerative diseases. Additionally, Cr and its cyclic analogues have been proposed for anti-cancer treatment. The mechanisms involved in these pleiotropic effects are still controversial and far from being understood. The reversible conversion of Cr and ATP into PCr and ADP by creatine kinase, generating highly diffusible PCr energy reserves, is certainly an important element. However, some protective effects of Cr and analogues cannot be satisfactorily explained solely by effects on the cellular energy state. Here we used mainly liposome model systems to provide evidence for interaction of PCr and PcCr with different zwitterionic phospholipids by applying four independent, complementary biochemical and biophysical assays: (i) chemical binding assay, (ii) surface plasmon resonance spectroscopy (SPR), (iii) solid-state (31)P-NMR, and (iv) differential scanning calorimetry (DSC). SPR revealed low affinity PCr/phospholipid interaction that additionally induced changes in liposome shape as indicated by NMR and SPR. Additionally, DSC revealed evidence for membrane packing effects by PCr, as seen by altered lipid phase transition. Finally, PCr efficiently protected against membrane permeabilization in two different model systems: liposome-permeabilization by the membrane-active peptide melittin, and erythrocyte hemolysis by the oxidative drug doxorubicin, hypoosmotic stress or the mild detergent saponin. These findings suggest a new molecular basis for non-energy related functions of PCr and its cyclic analogue. PCr/phospholipid interaction and alteration of membrane structure may not only protect cellular membranes against various insults, but could have more general implications for many physiological membrane-related functions that are relevant for health and disease.
Myostatin is a catabolic regulator of skeletal muscle mass. The purpose of this study was to determine the effect of resistance training for 8 weeks in conjunction with creatine supplementation on muscle strength, lean body mass, and serum levels of myostatin and growth and differentiation factor-associated serum protein-1 (GASP-1). In a double-blinded design 27 healthy male subjects (23.42+/-2.2 years) were assigned to control (CON), resistance training+placebo (RT+PL) and resistance training+creatine supplementation (RT+CR) groups. The protocol consisted of 3 days per week of training for 8 weeks, each session including three sets of 8-10 repetitions at 60-70% of 1 RM for whole-body exercise. Blood sampling, muscular strength testing and body composition analysis (full body DEXA) were performed at 0, 4th and 8th weeks. Myostatin and GASP-1 was measured. Resistance training caused significant decrease in serum levels of myostatin and increase in that of GASP-1. Creatine supplementation in conjunction with resistance training lead to greater decreases in serum myostatin (p<0.05), but had not additional effect on GASP-1 (p>0.05). The effects of resistance training on serum levels of myostatin and GASP-1, may explain the increased muscle mass that is amplified by creatine supplementation.
This study examined 12 wk of creatine (Cr) supplementation and heavy resistance training on skeletal muscle creatine kinase (M-CK) mRNA expression and the mRNA and protein expression of the myogenic regulatory factors Myo-D, myogenin, MFR-4, and Myf5.
Twenty-two untrained males were randomly assigned to either a control (CON), placebo (PLC), or Cr (CRT) group in a double-blind fashion. Muscle biopsies were obtained before and after training. PLC and CRT trained thrice weekly using 3 sets of 6-8 repetitions at 85-90% 1-RM on the leg press, knee extension, and knee curl exercises. CRT ingested 6 g.d-1 of Cr for 12 wk while PLC consumed the equal amount of placebo.
After training, M-CK mRNA expression, as well as myogenin and MRF-4 mRNA and protein expression, were found to be significantly greater for CRT compared with PLC and CON, whereas PLC was also significantly different from CON (P < 0.05). For Myo-D mRNA and protein, both CRT and PLC were significantly different from CON (P < 0.05), but CRT and PLC were not different from one another. No significant differences were located for Myf5 mRNA or protein (P > 0.05). M-CK mRNA was correlated with myogenin (r = 0.916) and MRF-4 (r = 0.883) protein (P < 0.05).
When combined with heavy resistance training, Cr supplementation increases M-CK mRNA expression, likely due to concomitant increases in the expression of myogenin and MRF-4. Therefore, increases in myogenin and MRF-4 mRNA and protein may play a role in increasing myosin heavy chain expression, already shown to occur with Cr supplementation.
We hypothesized that creatine supplementation would facilitate muscle anabolism by increasing the expression of growth factors and the phosphorylation of anabolic signaling molecules; we therefore tested the responses of mRNA for IGF-I and IGF-II and the phosphorylation state of components of anabolic signaling pathways p70(s6k) and 4E-BP1 to a bout of high-intensity resistance exercise after 5 d of creatine supplementation.
In a double-blind cross-over design, muscle biopsies were taken from the m. vastus lateralis at rest and 3 and 24 h postexercise in subjects who had taken creatine or placebo for 5 d (21 g x d(-1)). For the first 3 h postexercise, the subjects were fed with a drink containing maltodextrin (0.3 g x kg(-1) body weight x h(-1)) and protein (0.08 g x kg(-1) body weight x h(-1)).
After creatine supplementation, resting muscle expressed more mRNA for IGF-I (+30%, P < 0.05) and IGF-II (+40%, P = 0.054). Exercise caused an increase by 3 h postexercise in IGF-I (+24%, P < 0.05) and IGF-II (+48%, P < 0.05) and by 24 h postexercise in IGF-I (+29%, P < 0.05), but this effect was not potentiated by creatine supplementation. The phosphorylation states of p70(s6k) and 4E-BP1 were not affected by creatine at rest; phosphorylation of both increased (150-400%, P < 0.05) to similar levels under placebo and creatine conditions at 3 h postexercise plus feeding. However, the phosphorylation state of 4E-BP1 was higher in the creatine versus placebo condition at 24 h postexercise.
The increase in lean body mass often reported after creatine supplementation could be mediated by signaling pathway(s) involving IGF and 4E-BP1.
This study examined 12 wk of creatine (Cr) supplementation and heavy resistance training on muscle strength and myosin heavy chain (MHC) isoform mRNA and protein expression.
Twenty-two untrained male subjects were randomly assigned to either a control (CON), placebo (PLC), or Cr (CRT) group in a double-blind fashion. Muscle biopsies were obtained before and after 12 wk of heavy resistance training. PLC and CRT trained thrice weekly using three sets of 6-8 repetitions at 85-90% 1-RM on the leg press, knee extension, and knee curl exercises. CRT ingested 6 g.d-1 of Cr for 12 wk, whereas PLC consumed the equal concentration of placebo.
There were no significant differences for percent body fat (P > 0.05). However, for total body mass, fat-free mass, thigh volume, muscle strength, and myofibrillar protein, CRT and PLC exhibited significant increases after training when compared to CON (P < 0.05), whereas CRT was also significantly greater than PLC (P < 0.05). For Type I, IIa, and IIx MHC mRNA expression, CRT was significantly greater than CON and PLC, whereas PLC was greater than CON (P < 0.05). For MHC protein expression, CRT was significantly greater than CON and PLC for Type I and IIx (P < 0.05) but was equal to PLC for IIa.
Long-term Cr supplementation increases muscle strength and size, possibly as a result of increased MHC synthesis.
This study investigated resting concentrations of selected androgens after 3 weeks of creatine supplementation in male rugby players. It was hypothesized that the ratio of dihydrotestosterone (DHT, a biologically more active androgen) to testosterone (T) would change with creatine supplementation.
Double-blind placebo-controlled crossover study with a 6-week washout period.
Rugby Institute in South Africa.
College-aged rugby players (n = 20) volunteered for the study, which took place during the competitive season.
Subjects loaded with creatine (25 g/day creatine with 25 g/day glucose) or placebo (50 g/day glucose) for 7 days followed by 14 days of maintenance (5 g/day creatine with 25 g/day glucose or 30 g/day glucose placebo).
Serum T and DHT were measured and ratio calculated at baseline and after 7 days and 21 days of creatine supplementation (or placebo). Body composition measurements were taken at each time point.
After 7 days of creatine loading, or a further 14 days of creatine maintenance dose, serum T levels did not change. However, levels of DHT increased by 56% after 7 days of creatine loading and remained 40% above baseline after 14 days maintenance (P < 0.001). The ratio of DHT:T also increased by 36% after 7 days creatine supplementation and remained elevated by 22% after the maintenance dose (P < 0.01).
Creatine supplementation may, in part, act through an increased rate of conversion of T to DHT. Further investigation is warranted as a result of the high frequency of individuals using creatine supplementation and the long-term safety of alterations in circulating androgen composition. STATEMENT OF CLINICAL RELEVANCE: Although creatine is a widely used ergogenic aid, the mechanisms of action are incompletely understood, particularly in relation to dihydrotestosterone, and therefore the long-term clinical safety cannot be guaranteed.
Creatine supplementation is in widespread use to enhance sports-fitness performance, and has been trialled successfully in the treatment of neurological, neuromuscular and atherosclerotic disease. Creatine plays a pivotal role in brain energy homeostasis, being a temporal and spatial buffer for cytosolic and mitochondrial pools of the cellular energy currency, adenosine triphosphate and its regulator, adenosine diphosphate. In this work, we tested the hypothesis that oral creatine supplementation (5 g d(-1) for six weeks) would enhance intelligence test scores and working memory performance in 45 young adult, vegetarian subjects in a double-blind, placebo-controlled, cross-over design. Creatine supplementation had a significant positive effect (p < 0.0001) on both working memory (backward digit span) and intelligence (Raven’s Advanced Progressive Matrices), both tasks that require speed of processing. These findings underline a dynamic and significant role of brain energy capacity in influencing brain performance.
Supplementation with creatine-based substances as a means of enhancing athletic performance has become widespread. Until recently, however, the effects of creatine supplementation on cognitive performance has been given little attention. This study used a new form of creatine—creatine ethyl ester–to investigate whether supplementation would improve performance in five cognitive tasks, using a double-blind, placebo-controlled study.Creatine dosing led to an improvement over the placebo condition on several measures. Although creatine seems to facilitate cognition on some tasks, these results require replication using objective measures of compliance. The improvement is discussed in the context of research examining the influence of brain energy capacity on cognitive performance.
The purpose of this study was to examine the effect of creatine supplementation on the cognitive performance of elderly people. Participants were divided into two groups, which were tested on random number generation, forward and backward number and spatial recall, and long-term memory tasks to establish a baseline level. Group 1 (n = 15) were given 5 g four times a day of placebo for 1 week, followed by the same dosage of creatine for the second week. Group 2 (n = 17) were given placebo both weeks. Participants were retested at the end of each week. Results showed a significant effect of creatine supplementation on all tasks except backward number recall. It was concluded that creatine supplementation aids cognition in the elderly.
Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. Accordingly, the creatine kinase/phosphocreatine system plays a key role in cellular energy buffering and energy transport, particularly in cells with high and fluctuating energy requirements like neurons. Creatine kinases are expressed in the adult and developing human brain and spinal cord, suggesting that the creatine kinase/phosphocreatine system plays a significant role in the central nervous system. Functional impairment of this system leads to a deterioration in energy metabolism, which is phenotypic for many neurodegenerative and age-related diseases. Exogenous creatine supplementation has been shown to reduce neuronal cell loss in experimental paradigms of acute and chronic neurological diseases. In line with these findings, first clinical trials have shown beneficial effects of therapeutic creatine supplementation. Furthermore, creatine was reported to promote differentiation of neuronal precursor cells that might be of importance for improving neuronal cell replacement strategies. Based on these observations there is growing interest on the effects and functions of this compound in the central nervous system. This review gives a short excursion into the basics of the creatine kinase/phosphocreatine system and aims at summarizing findings and concepts on the role of creatine kinase and creatine in the central nervous system with special emphasis on pathological conditions and the positive effects of creatine supplementation.
Creatine plays a pivotal role in brain energy homeostasis, and altered cerebral energy metabolism may be involved in the pathophysiology of depression. Oral creatine supplementation may modify brain high-energy phosphate metabolism in depressed subjects.
Eight unipolar and two bipolar patients with treatment-resistant depression were treated for four weeks with 3-5 g/day of creatinemonohydrate in an open add-on design. Outcome measures were the Hamilton Depression Rating Scale, Hamilton Anxiety Scale, and Clinical Global Impression scores, recorded at baseline and at weeks 1, 2, 3 and 4.
One patient improved considerably after one week and withdrew. Both bipolar patients developed hypomania/mania. For the remaining seven patients, all scale scores significantly improved. Adverse reactions were mild and transitory.
This small, preliminary, open study of creatine monohydrate suggests a beneficial effect of creatine augmentation in unipolardepression, but possible precipitation of a manic switch in bipolar depression.
Creatine‘s effects on brain energy metabolism raise the possibility of developing a new therapeutic strategy in depression focusing on the treatment of metabolic hypoactive brain areas. Previous creatine augmentation studies in patients with major depression showed a beneficial effect. Eighteen patients (14 women) with major depression not responding to previous 3 weeks of antidepressant treatment were enrolled into a pilot, dose finding, 4-week double-blind parallel augmentation study where creatine monohydrate 5 or 10 g daily or placebo was added to ongoing SSRIs/SNRIs/NASA treatment. Rating scales included the Hamilton Depression Rating Scale and the Clinical Global Impression Severity scale. Overall, there was no difference between creatine administered at 5 or 10 g daily and its corresponding placebos. Two female patients on creatine augmentation, but none on the placebo, showed early improvement of more than 50% reduction in Hamilton Depression Rating Scale after 2 weeks of creatine treatment. No clinically relevant side effects were reported. This preliminary study seems to suggest that the strategy using creatine augmentation in majordepressive women showing no ‘real-life response’ to 3 weeks of treatment with SSRIs/SNRIs/NASA treatment is of no advantage compared with placebo. However, such creatine augmentation may still induce a more rapid response in a small subgroup of these female patients.
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