Creatine monohydrate is a supplement that helps in the production of energy (ATP) for short-term strength and power activities by increasing creatine in muscle, which is converted to creatine phosphate. Recent studies have demonstrated that supplementation with 25 g creatine per day for 5–6 d can significantly increase muscle creatine content (13–15,34) and enhance short-term high force/power exercise performance (2,5,9,34,35). Although there have been a number of creatine supplementation studies assessing physical performance, there are relatively few reports describing the potential for adverse side effects.
In a recent American College of Sports Medicine consensus statement summarizing the physiological and health effects of oral creatine supplementation, it was recommended that individuals wishing to control weight and who are subjected to strenuous exercise and/or hot environments should avoid creatine supplementation (31). However, no studies have examined the influence of creatine supplementation on fluid balance, sweat rates, or thermal stress in individuals exercising in the heat. Because many athletes practice and compete in high ambient temperature and/or humid conditions and are using creatine to enhance performance, it is important to study the physiological effects of creatine in such conditions. Our primary goal for this study was to examine the influence of short-term creatine supplementation on thermoregulatory responses to a brief bout of submaximal and maximal exercise in the heat.
At ambient temperature, cardiovascular (21,23,25) and renal (26,27) responses to exercise are not affected by creatine supplementation. However, no studies have examined physiological responses of creatine supplemented subjects to exercise with the added burden of high heat and high humidity. We tested the hypothesis that the cardiovascular, renal, and temperature regulation responses to the combined burdens of exercise and heat/humidity stress would be exacerbated by creatine supplementation. Acute creatine supplementation significantly increases body mass (34,35), which has been shown to be due primarily to water retention (37). We measured renin, angiotensin I, angiotensin II, arginine vasopressin, and aldosterone to obtain data on water regulatory hormonal responses. Because creatine supplementation has been shown to enhance peak power and mean power during high-intensity exercise after submaximal exercise (32), we hypothesized that power output after a submaximal exercise bout would be enhanced after creatine loading.
Two groups of subjects performed two identical experimental exercise protocols in the heat (T1 and T2) separated by 7 d of supplementation. Before experimental heat sessions, anthropometric measurements were obtained (height, weight, and skin-fold thickness). A maximal graded exercise test on a stationary cycle ergometer was performed at ambient temperature to obtain peak oxygen consumption using an automated online system. Inspired air volume was measured with a Parkinson-Cowen dry gas meter (Instrumentation Associates, New York, NY), and expired gases were continuously sampled from a mixing chamber for analysis of oxygen (Applied Electrochemistry, Sunnydale, CA) and carbon dioxide (Beckman LB-2, Schiller Park, IL). Gas analyzers were calibrated before each test with standard gases of known concentrations. Two days later, subjects performed a 20-min submaximal trial on a stationary cycle ergometer at ambient temperature to become familiarized with the exercise intensity used during subsequent cycle ergometer trials in the heat. Approximately 3 d later, subjects performed the first experimental cycle exercise protocol in a temperature- and humidity-controlled environmental chamber (T1).
After all baseline testing, subjects were matched according to physical characteristics and training status and then randomly assigned in a double-blind fashion to either a creatine (N = 10) or placebo (N = 10) group. After 7 d of creatine or placebo supplementation, subjects performed the same cycle exercise protocol in the environmental chamber under identical testing conditions (T2). A cross-over study was not utilized since the washout period required for muscle creatine concentrations to return to baseline is approximately 1 month (15). One month between treatments may have posed reproducibility problems due to possible changes in V̇O2peak resulting from training during the washout period. Further, the washout period for creatine has only been validated in a small number of studies that measured total creatine in muscle. A distribution curve has not been established to know whether some individuals require longer than 1 month. Further complicating cross-over studies is the possibility that some individuals may consume enough red meat in their habitual diet to maintain elevated muscle creatine stores during a washout period.
Twenty healthy men volunteered to participate in this investigation performed between the months of February and May. Only subjects that had never supplemented with creatine monohydrate or taken anabolic steroids (determined via a questionnaire) were eligible for participation, because the effects of prior use of creatine monohydrate or anabolic steroids on physiological responses to exercise in the heat are unknown. After matching and then randomly assigning subjects to creatine or placebo supplementation, no significant differences existed between groups in physical characteristics (Table 1). All subjects were informed of the purpose and possible risks of the investigation before signing an informed consent document approved by the Institutional Review Board at Ball State University and in adherence with the guidelines of the American College of Sports Medicine.
After the first exercise session in the heat, creatine subjects began consuming 0.3 g of creatine monohydrate per kilogram of body weight per day in capsule form divided into five equal dosages consumed every 2–3 h (Creatine Fuel®, Twin Laboratories, Inc., Hauppauge, NY). The placebo group ingested an identical looking and equivalent amount of placebo capsules (powdered cellulose) for 7 d. We recently reported this dosage pattern of creatine administration rapidly increased muscle creatine stores by 22% in men of similar physical characteristics to the subjects used in this study (34). In our experience, this is also a common dosage used by collegiate athletes to enhance performance.
The exercise protocol was performed in a temperature- and humidity-controlled environmental chamber at an ambient temperature of 37°C and 80% relative humidity on an upright cycle ergometer (modified Monark cycle ergometer, Varberg, Sweden). Nude body mass and resting blood and urine samples were obtained before exercise at ambient temperature. Subjects entered the chamber and sat on the cycle ergometer for 10 min before exercise. Heart rate, blood pressure, and rectal temperature were recorded after 10 min and then subjects began the protocol by exercising for 15 min at an intensity of 70% V̇O2peak and then 15 min at an intensity of 60% V̇O2peak (based on prior measurement of V̇O2peak). Ratings of perceived exertion (RPE) were recorded at 15 and 30 min of the exercise protocol using a 10-point Borg scale. After 30 min of continuous exercise, three consecutive 10-s maximal-effort sprints were performed separated by 50 s. Resistance was set at 0.735 N (0.075 kg) per kg of body mass. Flywheel revolutions were monitored via an electromagnetic detection system with printer interface during each 10-s bout. Total flywheel revolutions per second were recorded and used to calculate peak power (highest 1-s value) and mean power output for each 10-s bout. Repeat performance tests on the cycle ergometer in our laboratory have an intraclass correlation coefficient of >0.95. After the last sprint, subjects pedaled at 60 rev·min−1 against the flywheel inertial resistance for 3 min to avoid adverse symptomology (e.g., hypotension). Immediately after the cool down, subjects completely dried themselves of all sweat and a postexercise nude body mass was obtained. The change in body mass was used to calculate sweat rate (loss in body weight·time of exercise−1). A venous blood sample was obtained 10 min after exercise and postexercise urine was collected. Dietary intake was recorded the day before exercise before supplementation (T1) and reproduced the day before exercise after supplementation (T2). Hydration status was standardized by having subjects consume 5-mL water per kilogram body mass during the hour before exercise; no water or food was permitted during the exercise protocol. All subjects performed T1 and T2 at the same time of day in the morning to eliminate possible diurnal variations.
Heart rate was monitored using a Polar heart rate monitor (Port Washington, NY), and blood pressure was measured via brachial auscultation in the heat before exercise and after 10 and 20 min of exercise. Expired gases were collected for 1 min after 15 and 30 min of exercise, using a Douglas Bag setup. The volume of air in each bag was measured with a dry gas meter (Instrumentation Associates, New York, NY), and aliquots of air were sampled for oxygen and carbon dioxide, using the same system described for determination of V̇O2peak. Gas analyzers were calibrated before each test.
Rectal temperature was used as an index of core temperature. A flexible rectal thermistor was inserted 10 cm past the anal sphincter before the exercise session in the heat. Rectal temperature was recorded before exercise and at 5 min-intervals during the submaximal exercise on an Iso-Thermex system (Columbus Instruments, Columbus, OH) that was interfaced with an IBM compatible computer. A temperature-controlled water bath (verified with a mercury thermometer) was used to calibrate the rectal thermistor before each exercise session.
Nude body mass was determined with an electronic scale (Toledo Scale Corporation, Worthington, OH). Skin-fold thickness was obtained at seven sites with a Lange skin-fold caliper at the chest, mid-axillary, triceps, subscapular, abdominal, suprailiac, and thigh, using standard procedures (19). All skin-fold measurements were obtained on the right side by the same experienced investigator. The sum of seven skinfolds was used to calculate body density (16) and percent fat (28). Total body water was estimated via bioelectrical impedance analysis using a modified scale platform mounted with pressure electrodes in contact with the feet (TBF-105 Body Fat Analyzer, Tanita Corporation of America, Inc., Skokie, IL). Repeat total body water measurements obtained on 12 men on four occasions separated by 1 wk between tests demonstrated a coefficient of variation of 1.8%
Blood collection and analyses.
A preexercise venous blood sample was obtained from a forearm vein and collected into chilled tubes containing EDTA and appropriate preservatives. A postexercise blood sample was also obtained at 10 min postexercise. Blood samples were obtained in ambient temperature with subjects lying down for 7 min before the draw. All preexercise blood samples were obtained at the same time of the morning for each subject and after a 10-h overnight fast and abstinence from exercise for 24 h. Whole blood was used to determine hemoglobin in duplicate using the cyanmethemoglobin method at 540 nm (Sigma Diagnostics, St. Louis, MO), and hematocrit was analyzed in triplicate via standard microcapillary techniques and microcentrifugation. Percent changes in plasma volume from pre- to post-exercise were calculated from hemoglobin and hematocrit (10). Whole blood was processed and centrifuged at 3000 ×g, and the resultant plasma stored at −80°C until analyzed.
Cortisol and aldosterone were assayed in duplicate using a solid-phase 125I radioimmunoassay (RIA), and renin was assayed using a noncompetitive immunoradiometric assay (Diagnostic Systems Laboratory, Webster, TX) with a sensitivity of 0.5 pg·mL−1. Plasma for arginine vasopressin, angiotensin I, angiotensin II, and atrial peptide were preliminarily extracted using pretreated C18 separating columns (200 mg, equilibrated with 100% acetonitrile and 1% trifluoroacetic acid; Peninsula Laboratories, Belmont, CA) with a series of washes (1% trifluoroacetic acid and 60% acetonitrile in 1% trifluoroacetic acid). The eluant was evaporated under vacuum. A commercially available 125I ligand and antisera were used similar to methods used in previous studies (17,18). Arginine vasopressin concentrations were determined in duplicate using a double antibody 125I RIA (Diagnostic Systems Laboratory, Webster, TX) with a sensitivity of 0.5 pg·mL−1. Atrial peptide, angiotensin I, and angiotensin II concentrations were determined in duplicate via double antibody 125I RIA (Peninsula Laboratories, Belmont, CA). All samples for each hormone were determined in the same assay to avoid interassay variance and were thawed only once for each assay procedure. Intra-assay coefficients of variance for all assays were less than 5%. Values from extracted samples were all corrected for specific column recovery values.
Urine collection and analyses.
During the 7-d supplementation period, 24-h urine collections were obtained on days 1, 3, 5, and 7. In addition, urine collections were obtained pre- and post-exercise. Urine volumes were measured using a graduated cylinder and aliquots stored at −80°C in 15-mL polypropylene Falcon tubes. Sodium and potassium concentrations were measured using an automatic flame photometer (Model 09430-10, Instrumentation Laboratories, Lexington, MA). Creatinine concentrations for serum and 24-h urine were determined by using standard spectrophotometric techniques (Spectronic 501, Milton Roy Co., Rochester, NY; Jaffe method).
Nutrition assessment and side effects.
All subjects consumed a typical diet and were instructed to maintain their habitual eating and drinking patterns for the duration of the study. Before the beginning of the study, each subject was instructed by the same registered dietitian and provided with specific verbal and written instructions and procedures for reporting detailed food and beverage (including water) consumption during the supplementation period. To assess potential side effects and subjective changes in body function to the supplementation regimen and the exercise session in the heat, a questionnaire used in prior creatine studies by our laboratory (34,35) was provided to subjects. The questionnaire asked subjects to document changes in appetite, thirst, skin, muscle soreness, muscle cramping, stomach distress, diarrhea, flatulence, headache, sex drive, sleepiness, nervousness, and aggression.
Statistical evaluation of the data was accomplished by using a two-way analysis of variance (ANOVA) with repeated measures design. When a significant F-value was achieved, a Fisher’s LSD test was used to locate the pairwise differences between means. Change scores for body mass and body water were analyzed with independent t-tests. Total area under curve (AUC) calculations for temperature responses (0, 5, 10, 15, 20, 25, and 30 min values) to exercise in the heat were calculated using the trapezoidal method. Statistical power ranged from 0.78 to 0.80 at a P-value equal to 0.05 (nQuery Advisor®, Statistical Solutions, Saugus, MA). The level of significance was set at P ≤ 0.05. All values presented are mean ± SE.
Body mass and body water are presented in Table 2. There was a significant increase in body mass after 1 wk in creatine (0.75 kg) and no change in placebo (0.00 kg). Total body water significantly increased after 1 wk in the creatine (0.4 kg) but not the placebo (−0.1 kg) group. When expressed as a percentage of total body water, there were no significant changes after supplementation in either group.
All subjects completed the submaximal and maximal exercise protocol at the specified relative intensities. Exercise intensities were verified by oxygen consumption collected during the submaximal exercise protocol. There were no adverse effects reported for any of the subjects in either the creatine or placebo groups to the supplementation protocol or exercise in the heat. This included no reports of muscle cramping or other musculoskeletal complaints. There were similar significant reductions in body mass due to exercise in the heat for the creatine and placebo groups before (11.69 ± 1.45 and 11.66 ± 2.47 mL·min−1, respectively) and after (11.70 ± 1.45 and 11.66 ± 2.47 mL·min−1, respectively) 1 wk of supplementation. Sweat rates during exercise were thus not significantly different between the creatine and placebo groups before (13.00 ± 0.88 and 14.63 ± 1.31 g·m−2·min−1, respectively) and after (12.24 ± 0.88 and 14.36 ± 1.15 g·m−2·min−1, respectively) 1 wk of supplementation. There were significant decreases in plasma volume in the creatine and placebo groups before (−11 ± 3% and −5 ± 2%, respectively) and after (−11 ± 1% and −7 ± 3%, respectively) supplementation, but the responses were not significantly different between groups.
Cardiovascular responses to exercise are shown in Table 3. There were no significant differences in resting heart rate, systolic and diastolic blood pressure, and mean arterial pressure (MAP). Heart rate responses to exercise were similar between groups before and after 1 wk of supplementation except for a significantly higher 20-min heart rate during presupplementation exercise in the placebo group. Systolic blood pressure, diastolic blood pressure, and MAP responses were not significantly different between groups before or after 1 wk of supplementation. Perceived exertion was similar between creatine and placebo, and in all cases was 9 or 10 after 30 min of exercise.
Rectal temperature responses are shown in Table 4. Rectal temperature significantly increased during exercise and exceeded 38.3°C for both groups before and after supplementation, indicating a severe thermoregulatory stress for all subjects. There were no significant differences in the rectal temperature response at any time point or the AUC after 1 wk of supplementation in either group.
Indices of kidney function are presented in Table 5. Although urinary volumes tended to be greater in creatine subjects, only day 3 was significantly greater than placebo. Data analyzed from 7-d diet records showed that during the supplementation period, mean fluid intake was 3.2 ± 0.6 and 2.1 ± 0.3 L·d−1 for the creatine and placebo groups, respectively. Sodium, potassium, and creatinine 24-h excretion rates were not significantly different between groups at any time during supplementation. There was a significant increase in serum creatinine after 1-wk of supplementation in the creatine group (13%) but not the placebo group. There were no significant differences between creatine and placebo groups in urine production rate or sodium and potassium excretion rates during exercise.
Resting preexercise concentrations of cortisol, aldosterone, renin, angiotensin I and II, atrial peptide, and arginine vasopressin were not significantly different after 1 wk of supplementation in either group. There were significant increases in all hormones in response to exercise. The exercise responses were similar before and after supplementation with the exception of a significantly greater exercise-induced increase in aldosterone after creatine supplementation (Table 6).
Supplementation with placebo had no significant effect on peak and mean power. However, a significant interaction effect detected by the ANOVA indicated that peak power for each of the three sprints was increased after supplementation with creatine (Fig. 1). Mean power during sprints 1, 2, and 3 were 688 ± 58, 687 ± 58, and 665 ± 49 respectively, before creatine supplementation and 788 ± 58, 753 ± 48, and 710 ± 52, respectively, after creatine supplementation. Mean power for the first sprint only was significantly increased after creatine supplementation.
The effects of creatine loading on thermoregulatory responses to exercise in the heat have not been documented. Thus, this study provides several novel findings related to acute cardiovascular, renal, temperature, and fluid-regulatory hormonal responses to the dual stress of exercise and heat/humidity. Importantly, we did not observe any evidence that 1 wk of creatine supplementation adversely affects physiology at rest or during 35 min of intense exercise in the heat, indicating that creatine supplementation may not pose a threat to thermoregulation during brief exposure to exercise in hot and humid conditions. Under most circumstances, athletes would be exposed to the warm environment for longer periods, and thus sweat loss and dehydration would be greater. We cannot comment on the potential effects of creatine supplementation on thermoregulation during periods lasting longer than 35 min in the heat.
The increase in body mass after 1 wk of creatine supplementation is consistent with our previous work (34,35) and that of others (3,12,22). The increase in body mass after short-term creatine supplementation has been shown to be a result of intracellular water retention (37). According to our data, the significant absolute increase in body water is in proportion to the increase in body mass such that percent body water is not different after creatine supplementation.
Consistent with our findings, short-term creatine supplementation has been shown to have no effect on resting heart rate or blood pressure (21,23,25,29). Ejection fraction assessed via echocardiography was not affected after creatine supplementation in patients suffering from chronic heart failure (11). Our data showed similar decreases in plasma volume during exercise in the heat before and after creatine supplementation, indicating no effect of creatine on movement of fluid out of the plasma during short-term exercise in the heat. We showed no effect of creatine on exercise heart rate and blood pressure responses. Peyrebrune et al. (25) also showed no significant effect of creatine supplementation on maximal heart rate responses to sprint swimming. To our knowledge, these are the first data to report blood pressure responses during exercise after supplementation and show no effect of creatine even with the added heat stress.
These are the first data reporting resting or exercise body temperature responses to acute creatine supplementation. The presupplementation and postsupplementation temperature responses to exercise in the heat were nearly identical in creatine subjects, indicating that creatine does not significantly influence temperature regulation during 35 min of exercise in a hot and humid environment.
Hultman et al. (15) observed a reduction in urine volume in men during short-term creatine supplementation. In our study, there were large interindividual variations and group differences in the average fluid ingested per day and subsequent urine volumes. Thus, the larger urinary volumes in creatine subjects were most likely due to the greater fluid intake in this group, especially by two individuals who habitually consumed between 5 and 7 L of fluid per day. These were habitual water consumption patterns as no subjects reported any changes in thirst or appetite during the experimental period.
We observed no abnormal responses in several measures of renal function during rest and exercise, except for a small but significant increase in serum creatinine. Poortmans et al. (27) also demonstrated a small increase in serum creatinine after creatine loading. The small but statistically significant increase in serum creatinine is within normal ranges for healthy athletes. As muscle creatine breakdown has been shown to occur at a constant rate (1.6% per day), this small increase in creatinine is likely a result of the larger muscle creatine pool available for breakdown after creatine supplementation. Urine sodium and potassium excretion rates were similar between creatine and placebo during the 7 d of supplementation and during exercise in the heat. These are the first data to measure renal function during exercise after 1 wk of creatine supplementation and indicate that creatine supplementation does not alter normal renal responses to brief exercise in the heat.
There are no published data on the resting and exercise-induced responses of water regulatory hormones to creatine supplementation. Atrial peptide, arginine vasopressin, aldosterone, renin activity, and angiotensin I and II were used in this investigation to examine the regulatory influences from the cardiovascular (i.e., atrial peptide from the atrial cardiocytes) and renal systems. The primary finding in this study was that creatine supplementation does not result in any dramatic differences in the responses of several stress-related and fluid regulatory hormones at rest or with exercise stress in the heat, except for a small but significantly higher postexercise aldosterone response. The magnitude of difference in the exercise-induced aldosterone concentrations between the two experimental conditions, although statistically significant, were within normal variation of the hormone’s response to exercise stress in the heat (8,18). The higher exercise-induced concentrations of aldosterone remain unclear as similar increases in the concentrations of all components of the renin-angiotensin-aldosterone cascade were observed under both experimental conditions. The higher aldosterone response may have been a result of the higher intensity of exercise performed during the cycling sprint performance after creatine supplementation. The magnitude of the aldosterone response to exercise has been shown to be sensitive to small increases in intensity (1).
The significant exercise-induced hormonal responses to submaximal followed by surpramaximal bouts of exercise in this study are consistent with the literature examining atrial peptide, arginine vasopressin, renin activity, aldosterone, and angiotensin II (8,20,24,30). Plasma cortisol concentrations increased significantly from rest in the present study in both groups, indicating similar glucoregulatory responses at the level of the adrenal gland under both conditions. Creatine supplementation did not have any effect on the cortisol response to cycle exercise in the heat, which is consistent with our prior study demonstrating no effect of creatine supplementation on the cortisol or testosterone response to heavy resistance exercise (36).
Improved power output during repeated all-out cycling (<30 s) after short-term creatine supplementation is consistent with the findings of many (2,5,9) but not all (4,6,7) creatine studies. Few studies have assessed power after a submaximal exercise bout as in this study. Creatine loading enhanced peak power and mean power during each of five 10-s cycle sprints separated by 2 min performed after a 2.5-h simulated cycle race (32). Our data add to the literature by demonstrating that short-term creatine supplementation can enhance repeated 10-s cycle sprint performance after submaximal exercise in the heat. Creatine supplementation has been shown to attenuate ATP degradation as measured indirectly by blood ammonia and hypoxanthine accumulation after brief maximal exercise, indicating an enhanced ability to match ATP supply with ATP demand (5,22). An enhanced rate of phosphocreatine resynthesis during recovery between bouts may have contributed to the improved power in this study during bouts 2 and 3 (13). However, recent data indicate that this is probably not the primary mechanism for increased performance (33).
In trained athletes creatine supplementation has little impact on the multitude of hormonal effects involved in maintaining homeostatic control of temperature, electrolytes, fluid volume, and blood pressure. The time course of the hormonal changes with creatine supplementation remain to be studied but by the end of a 7-d loading period no significant alterations in this system that would create concern for the welfare of the athlete during brief exposure to heat exists under controlled conditions. Creatine supplementation did augment cycle performance in the heat.
We acknowledge a highly motivated group of subjects who made this investigation possible. We also acknowledge the support for this work by a grant from the National Collegiate Athletic Association.
William B. Farquhar is currently at the Laboratory for Cardiovascular Research, HRCA Research and Training Institute, Harvard Medical School, Boston, MA 02131.
Address for correspondence: Jeff S. Volek, Ph.D., R.D., Assistant Professor, The Human Performance Laboratory, Ball State University, Muncie, IN 47306; E-mail: [email protected]
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