Creatine supplementation influences substrate utilization at rest
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J Appl Physiol 93: 2018–2022, 2002.
First published August 16, 2002; 10.1152/japplphysiol.01170.2001.
Creatine supplementation influences substrate
utilization at rest
M. ERIK HUSO,1 JEFFREY S HAMPL,1 CAROL S. JOHNSTON,1 AND PAMELA D. SWAN2
Departments of 1Nutrition and 2Exercise and Wellness,
Arizona State University, Mesa, Arizona 85212
Received 27 November 2001; accepted in final form 5 August 2002
Huso, M. Erik, Jeffrey S Hampl, Carol S. Johnston, been too insensitive to quantify the small changes in
and Pamela D. Swan. Creatine supplementation influ- metabolic measures during exercise and recovery that
ences substrate utilization at rest. J Appl Physiol 93: could potentially occur with creatine supplementation.
2018–2022, 2002. First published August 16, 2002; 10.1152/ There may be other factors that confound the measure-
japplphysiol.01170.2001.—The influence of creatine supple-
ment of substrate utilization after acute exercise, such
mentation on substrate utilization during rest was investi-
gated using a double-blind crossover design. Ten active men as lactate concentration, that may mask any change in
participated in 12 wk of weight training and were given substrate. Thus a more steady-state measurement,
creatine and placebo (20 g/day for 4 days, then 2 g/day for 17 such as during rest, is needed.
days) in two trials separated by a 4-wk washout. Body com- The effect of creatine supplementation on substrate
position, substrate utilization, and strength were assessed utilization at rest has not been sufficiently investi-
after weeks 2, 5, 9, and 12. Maximal isometric contraction [1 gated. Because fat is the primary fuel oxidized during
repetition maximum (RM)] leg press increased significantly inactivity, measuring the respiratory exchange ratio
(P ⬍ 0.05) after both treatments, but 1-RM bench press was (RER) at rest could indicate whether fatty acid oxida-
increased (33 ⫾ 8 kg, P ⬍ 0.05) only after creatine. Total body tion is suppressed as a result of elevated levels of
mass increased (1.6 ⫾ 0.5 kg, P ⬍ 0.05) after creatine but not creatine phosphate in the system. A shift in substrate
after placebo. Significant (P ⬍ 0.05) increases in fat-free
mass were found after creatine and placebo supplementation
utilization toward lower fat oxidation could lead to a
(1.9 ⫾ 0.8 and 2.2 ⫾ 0.7 kg, respectively). Fat mass did not concomitant change in body composition with in-
change significantly with creatine but decreased after the creased body fat stores. On the basis of anecdotal
placebo trial (⫺2.4 ⫾ 0.8 kg, P ⬍ 0.05). Carbohydrate oxida- evidence of weight gain, including a lack of fat loss, in
tion was increased by creatine (8.9 ⫾ 4.0%, P ⬍ 0.05), persons taking creatine, a four-person pilot study was
whereas there was a trend for increased respiratory ex- carried out to determine whether creatine had any
change ratio after creatine supplementation (0.03 ⫾ 0.01, effect on substrate utilization. The results were en-
P ⫽ 0.07). Changes in substrate oxidation may influence the couraging, which led the authors to pursue the present
inhibition of fat mass loss associated with creatine after study. Thus we hypothesized that creatine supplemen-
weight training. tation would result in a shift in substrate utilization at
substrate oxidation; respiratory exchange ratio; carbohy- rest toward greater carbohydrate oxidation and less fat
drate; phosphate oxidation, indicated by a rise in the RER.
METHODS
A REPORTED EFFECT OF supplementation is
CREATINE
Subjects. In a double-blind, placebo-controlled crossover
weight gain (7, 10, 11, 21). Various mechanisms have design, 10 healthy, nonsmoking, recreationally active male
been proposed, including intramuscular water reten- subjects (Table 1) were recruited from a campus population
tion (8, 22) and increased muscle growth (7, 11). Only (Fig. 1). All subjects were free from chronic diseases and were
one known study has assessed the effect of creatine not regularly taking prescription medications. Moreover, all
supplementation on substrate utilization. Stroud et al. subjects participated in moderate physical activity at least
(20) examined the effect of creatine supplementation three times per week, were not vegetarians, were not taking
(20 g/day for 5 days) on respiratory gas exchange dur- any ergogenic aids, and had never supplemented with crea-
ing exercise and 15 min of recovery. Subjects ran on a tine. The study was approved by the Human Subjects Insti-
tutional Review Board at Arizona State University, and all
treadmill at 50–90% maximal O2 consumption for 6 subjects gave their voluntary and informed consent before
min at each of five intervals while gas samples were participation.
collected during the final 30 s at each workload. The Diet. Subjects were instructed to maintain their normal
results indicated that creatine had no effect on respi- diet throughout the study, except to limit consumption of
ratory gas exchange during exercise or recovery. The caffeinated beverages to two or fewer servings per day. Ran-
authors explained that the measurements could have
The costs of publication of this article were defrayed in part by the
Address for reprint requests and other correspondence: J. S payment of page charges. The article must therefore be hereby
Hampl, Dept. of Nutrition, Arizona State University, 7001 E. Wil- marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734
liams Field Rd., Mesa, AZ 85212. solely to indicate this fact.
2018 8750-7587/02 $5.00 Copyright © 2002 the American Physiological Society http://www.jap.orgCREATINE SUPPLEMENTATION AFFECTS SUBSTRATE UTILIZATION 2019
Table 1. Baseline physical characteristics of subjects Table 2. Exercise protocol
Age, yr 24 ⫾ 1 Monday Wednesday Friday
Height, cm 71 ⫾ 1
Mass, kg 74 ⫾ 2 Smith machine squats Leg press Hack squats
BMI, kg/m2 22.9 ⫾ 0.7 Leg curls Lunges Leg extensions
Bench press Heal raise Leg curl (seated)
Values are mean ⫾ SE (n ⫽ 10). BMI, body mass index. Row (machine) Behind neck press Bench press
DB shoulder press DB row Seated cable row
Wide grip pulldown Triceps extension Shoulder press
dom 24-h recalls were conducted via telephone at baseline Abdominal crunch Alternating DB curls Body weight pull-ups
and once during each test period to ensure that dietary Abdominal crunch Abdominal crunch
intake remained normal. Food records were reviewed by a
registered dietitian and analyzed using the Genesis R & D All exercises were performed in 3 sets of 8–10 repetitions, with
60–120 s of rest between sets. DB, dumbbell.
software (version 6.01, 1997, Esha Research, Salem, OR).
Exercise. Before initiation of creatine supplementation,
subjects participated in a familiarization session and 2 wk of min) using the Weir equation: 3.941 [V̇O2 (l/min)] ⫹ 1.106
weight training. Subjects were then tested twice to deter- [V̇CO2 (l/min)] ⫽ kcal/min, where V̇O2 is volume of O2 con-
mine baseline 1 repetition maximum (RM) for bench press sumed and V̇CO2 is volume of CO2 expired. The calculation of
and leg press. All 1-RM tests were performed on the same the RER is used to estimate the relative contribution of
equipment (CYBEX International, Medway, MA) and over- carbohydrate or fat to energy metabolism and represents the
seen by the same trained technician. Subjects followed an ratio of the metabolic gas exchange (i.e., V̇CO2/V̇O2). The
exercise program adapted from a protocol previously shown chemical differences inherent in the various substrates (fats,
to increase strength and body mass in subjects supplement- carbohydrates, and proteins) dictate the amount of O2 re-
ing with creatine and/or placebo (21) (Table 2). quired and the amount of CO2 produced specifically for each
Respiratory measures. On the evenings before all RER molecule’s full oxidation. Thus, depending on the substrate
testing (end of weeks 2, 5, 9, and 12), subjects consumed the metabolized, V̇CO2/V̇O2 will vary.
same self-selected meal to standardize the immediate effect Urinary analysis. Twenty-four-hour urine samples were
of diet on respiratory exchange. Subjects were instructed to collected before each RER measurement. Urine was analyzed
avoid all food and drink (excluding water) for 12 h until the for urea nitrogen and creatinine by colorimetric spectropho-
morning RER measurement. No subjects exercised within tometry to measure any changes in total body protein mass,
24 h of their RER test. to determine creatine uptake on the basis of the assumption
Subjects were tested between 5 and 9 AM, and each indi- that urinary creatinine clearance increases proportionally to
vidual subject was tested at the same time of day for each muscle creatine uptake (8), and to allow for the protein RER
trial. On arrival at the laboratory, subjects were positioned in determination. The samples were collected, stored, and ana-
a reclining chair and habituated to the open-circuit spirom- lyzed by standard laboratory kits (Sigma Chemical, St.
etry metabolic analysis apparatus for 20 min. A respiratory Louis, MO).
mask was placed over the subject’s face and carefully checked Body composition. Baseline body weight and body density
and sealed to prevent air leakage. Before subject testing, the were determined using whole body plethysmogrophy (Bod
O2 and CO2 analyzers were calibrated by N2 and two primary Pod, Life-Measurement Instruments, Concord, CA). The Bod
standard gases accurate to 0.01%. The pneumotachometer Pod uses whole body densitometry to determine body fat
was calibrated using a 3-liter syringe to deliver fixed volumes percentage using the Siri equation (2). The Bod Pod has been
at variable flow rates. Metabolic and RER measures were shown to be a reliable and valid tool for measuring body
done by indirect calorimetry in a temperature-controlled (20– composition (2, 3, 12, 13). Subjects were directed to wear a
23°C), quiet, dimly lit room. Subjects were awake, still, and Lycra swim cap and tight-fitting Lycra/spandex shorts or
quiet during the measurement. Metabolic measurements swimming briefs for each trial. Measurements were taken
were obtained by using a two-way nonrebreathing respira- according to standard manufacturer procedures (2, 12). Ad-
tory valve (Hans Rudolph, Kansas City, MO) interfaced with ditionally, lung volume was measured using a mouthpiece
a MAX-1 metabolic cart (Physiodyne Instrument, Quogue, and tube. The initial lung volume was used for each subse-
NY). After the 20-min habituation period, resting RER was quent test. All tests were performed by the same technician
estimated from a mean of 20 min of continuous gas sampling. immediately after the RER test.
Mean values of O2 and CO2 over each collection period Creatine supplementation. In a double-blind manner, sub-
were used in determining resting metabolic rate (RMR, kcal/ jects were randomly assigned creatine monohydrate powder
Fig. 1. Crossover design. Subjects were divided into 2 groups: group 1 (solid line) was supplemented with creatine
during weeks 3–5 and, after the 4-wk washout, ingested placebo during weeks 10–12; group 2 (dashed line) ingested
placebo during weeks 3–5 and, after the 4-wk washout, was supplemented with creatine during weeks 10–12. All
data were then combined to create a creatine group and a placebo group.
J Appl Physiol • VOL 93 • DECEMBER 2002 • www.jap.org2020 CREATINE SUPPLEMENTATION AFFECTS SUBSTRATE UTILIZATION
(a gift from X-Rated, Hi-Health, Scottsdale, AZ; 20 g creatine/ Table 4. Changes in substrate utilization at rest
day for 4 days, then 2 g creatine/day for 17 days) or a placebo
similar in appearance and taste (20 g maltodextrine for 4 Creatine Placebo
days, then 2 g for 17 days). Subjects were instructed to mix Before After Before After
the powder in juice or water. Also, subjects were required to
participate in resistance training at least three times per RER 0.78 ⫾ 0.01 0.81 ⫾ 0.02* 0.77 ⫾ 0.01 0.78 ⫾ 0.01
week and to keep a workout log. Subjects were required to RMR, kcal 1,890 ⫾ 73 1,869 ⫾ 58 1,960 ⫾ 82 1,947 ⫾ 60
submit their workout logs, and compliance was determined Fat, % 63.2 ⫾ 4.5 54.4 ⫾ 5.8 69.8 ⫾ 3.8 62.3 ⫾ 4.1
by the trained technician. Carbohydrate,
% 21.6 ⫾ 3.9 30.5 ⫾ 5.7† 18.6 ⫾ 3.5 22.4 ⫾ 4.3
At the end of 3 wk, subjects were tested for changes in
Protein, % 15.2 ⫾ 2.3 15.1 ⫾ 2.7 11.6 ⫾ 1.8 15.3 ⫾ 1.9
1-RM bench and leg press, body composition, and RER. After
a 4-wk washout period (6, 8), where supplementation was Values are means ⫾ SE (n ⫽ 10). RER, respiratory exchange ratio,
terminated but exercise continued, subjects were reassigned (protein-adjusted); RMR, resting metabolic rate. Fat, carbohydrate,
creatine or placebo and were tested again for a baseline and protein values represent percent participation of substrate in
measurement. After 3 wk of creatine or placebo, subjects total energy utilization. * P ⫽ 0.07 vs. before creatine. † P ⬍ 0.05 vs.
returned to the laboratory for testing (Fig. 1). before creatine.
Statistics. Values are means ⫾ SE. Data analyses were
performed on the Statistical Package for the Social Sciences
for Windows (version 10.0, 2000, SPSS, Chicago, IL). A gen-
(from 87 to 91 kg, P ⬍ 0.01) and leg press (from 280 to
eral linear model repeated-measures analysis was used to 313 kg, P ⬍ 0.01), whereas subjects on placebo had
compare differences between means over the course of the significant increases only with leg press (from 300 to
study. Order effects were determined by using a “dummy” 314 kg, P ⬍ 0.05).
variable and assessing a trial-by-time interaction in the Respiratory measures. There were no significant
model. Post hoc comparisons were done by least significant changes in RER for creatine or placebo (Table 4). The
differences because of the small number of pairwise compar- RER of the creatine group approached significance
isons. P ⬍ 0.05 was considered significant. (P ⫽ 0.07) as RER increased from 0.78 ⫾ 0.01 to 0.81 ⫾
0.02. Carbohydrate utilization, as a percentage of total
RESULTS
energy utilization, increased significantly in the crea-
No negative side effects were reported in subjects tine group (from 21.6 to 30.5%, P ⬍ 0.05). Changes in
taking creatine. For all measures, order effects were RMR were not statistically significant.
examined but were never significant. Energy intakes Urinary analysis. After 3 wk of creatine supplemen-
remained consistent throughout the duration of the tation, there was a significant increase in creatinine
study. With 3 wk of creatine supplementation, body clearance (from 1.3 to 1.8 g/day, P ⬍ 0.05) but no
mass increased significantly from 73.6 to 75.2 kg, a significant change during placebo use (Table 5). There
2.2% increase (P ⬍ 0.05). There was no significant were no significant differences in urea nitrogen mea-
change in body mass during placebo use (Table 3). sures.
Body composition. Fat-free mass (FFM) increased
DISCUSSION
after the weight-lifting program regardless of treat-
ment [from 63.1 to 65.0 kg with creatine (P ⬍ 0.05) and Previous research has indicated that subjects taking
from 63.2 to 65.4 kg with placebo (P ⬍ 0.01)]. No creatine supplements experienced a significant in-
significant differences in fat mass (FM) or percent body crease in weight gain (4, 11, 21). Researchers have
fat were observed in the creatine group. However, looked to identify the source of weight gain to deter-
percent body fat (from 15.6 to 12.4%, P ⬍ 0.01) and FM mine whether it is due to an increase in FFM or merely
(from 12.0 to 9.6 kg, P ⬍ 0.05) decreased significantly an increase in water (7). In accordance with existing
during placebo use. data, body mass increased significantly in subjects
Strength. Subjects in the creatine group experienced taking creatine during the course of this study. Signif-
significant increases in strength with bench press icant gains in FFM were shown after both treatments;
however, only the placebo group lost a significant
amount of FM and showed a significant decrease in
Table 3. Effect of creatine supplementation on body percent body fat. The ratio of FM to FFM significantly
composition and strength decreased during the placebo trial but not during the
Creatine Placebo creatine trial. Thus this study supports earlier studies
Before After Before After
Mass, kg 73.6 ⫾ 2.3 75.2 ⫾ 2.5* 75.2 ⫾ 2.5 74.8 ⫾ 2.4 Table 5. Results of urinary analysis
Body fat, % 14.0 ⫾ 1.5 13.3 ⫾ 1.2 15.6 ⫾ 1.6 12.4 ⫾ 1.2§
Fat-free mass, kg 63.1 ⫾ 1.1 65.0 ⫾ 1.8* 63.2 ⫾ 1.4 65.4 ⫾ 1.8§ Creatine Placebo
Fat mass, kg 10.7 ⫾ 1.4 10.0 ⫾ 1.2 12.0 ⫾ 1.5 9.6 ⫾ 0.9† Before After Before After
1-RM bench press,
kg 87 ⫾ 4 91 ⫾ 3‡ 90 ⫾ 4 92 ⫾ 4 Creatinine 1.3 ⫾ 0.2 1.8 ⫾ 0.2* 1.1 ⫾ 0.2 1.5 ⫾ 0.2
1-RM leg press, kg 280 ⫾ 19 313 ⫾ 22‡ 300 ⫾ 18 314 ⫾ 18† Urea nitrogen 9.7 ⫾ 1.3 10.6 ⫾ 2.1 8.0 ⫾ 1.4 10.9 ⫾ 1.4
Values are mean ⫾ SE (n ⫽ 10). RM, repetition maximum. * P ⬍ Values are means ⫾ SE in g/day. Normal values are 1.1–2.8 g/day
0.05 vs. before creatine. † P ⬍ 0.05 vs. before placebo. ‡ P ⬍ 0.01 vs. for creatine and 9.3–16.2 g/day for urea nitrogen. * P ⬍ 0.05 vs.
before creatine. § P ⬍ 0.01 vs. before placebo. before creatine.
J Appl Physiol • VOL 93 • DECEMBER 2002 • www.jap.orgCREATINE SUPPLEMENTATION AFFECTS SUBSTRATE UTILIZATION 2021
that creatine supplementation increases body mass fructokinase enzyme, promoting glucose oxidation (1).
with resistance training and indicates that creatine The increased flux of glucose oxidation results in in-
supplementation does not enhance percent body fat creased levels of malonyl-CoA (23).
loss in recreationally active men (4, 11, 15, 21). The Malonyl-CoA is a known regulator of fatty acid oxi-
placebo group experienced the expected response to dation (9, 19, 23). As the first committed intermediate
resistance training (16), i.e., they became leaner, of fatty acid synthesis, malonyl-CoA is a powerful in-
whereas the creatine group experienced an inhibition hibitor of the carnitine palmitoyltransferase (CPT I)
of this expected fat loss. enzyme system responsible for shuttling fatty acids
Francaux and Poortmans (7) proposed that in- into the mitochondria for oxidation (17, 23). When
creased myosin synthesis could be the mechanism be- glucose levels decline, malonyl-CoA also declines, al-
hind the ergogenic effect of creatine on exercise. How- lowing for increased fatty acid oxidation. Concentra-
ever, our data show that the increase in FFM was tions of malonyl-CoA drop during exercise and in the
similar in subjects taking creatine or placebo. In addi- fasted state, relieving the inhibition of CPT I. This
tion, those supplementing with creatine experienced
decrease in CPT I allows for an increased rate of fatty
significantly greater gains in 1-RM bench press and leg
acid oxidation as fats become available (23). The deple-
press. Therefore, although it was not measured di-
tion of ATP stores and subsequent increase in Pi during
rectly, we deduce that the ergogenic effect of creatine
on exercise performance must be from a mechanism activity result in an activation of the enzyme phospho-
other than increased myosin synthesis. fructokinase, causing an influx of carbohydrate to be
Consistent with these body composition data, we also oxidized. The infusion of glucose into exercising rats
found a trend for change in RER (P ⫽ 0.07) that has been shown to terminate the decline in malonyl-
supports the difference in FM between the creatine and CoA (5). Therefore, a promotion of glucose oxidation
placebo groups. (Post hoc power analysis indicated that from elevated levels of Pi could in theory suppress fatty
a sample of 12 would have been needed for statistical acid oxidation. However, research has shown that Pi
significance.) Although there was no significant change levels return to normal in the rested state after cre-
in RER during placebo administration, the increase in atine loading (18).
RER among creatine subjects approached statistical A more likely rationale would be the improved insu-
significance, indicating that subjects utilized a greater lin sensitivity and antihyperglycemic activity that
percentage of carbohydrate than fat during creatine creatine analogs have been shown to possess (14). Al-
supplementation. The difference in carbohydrate oxi- though the mechanism is unknown, 3-guanidinopropi-
dation before vs. after creatine was significant (P ⫽ onic acid administered to KKAy mice (a non-insulin-
0.05; Fig. 2). This finding is notable, inasmuch as it is dependent diabetes mellitus model) resulted in
the first time that the effect of creatine on resting RER augmented glucose uptake by the muscle tissue (14).
has been examined. As a gaunidino analog to 3-guanidinopropionic acid,
At the onset of exercise, with resistance training, elevated levels of creatine could potentially exert a
and during transitions from lower to higher intensity similar glycemic response, resulting in increased car-
exercise when energy demand is greater than energy bohydrate utilization by muscle tissue at rest.
production from aerobic sources, creatine phosphate is In conclusion, subjects supplementing with creatine
a readily available short-term fuel to produce ATP. The experienced greater gains in 1-RM bench press, 1-RM
products of creatine phosphate hydrolysis include free leg press, and weight gain than those using placebo.
creatine and Pi. Pi is a key activator of the phospho- We found that the increase in FFM was nearly identi-
cal in subjects taking creatine or placebo. However, the
results demonstrate that individuals taking creatine
may reduce their ability to lose FM in response to
exercise training. The results suggest that creatine
loading may inhibit the normal fat loss that occurs in
healthy active men implementing a strength-training
program. Moreover, for the first time, it was shown
that creatine supplementation led to a trend for in-
creased RER at rest, a potential mechanism for the
impaired fat loss. These conclusions affirm our hypoth-
esis that creatine supplementation would result in a
shift in substrate utilization at rest toward greater
carbohydrate oxidation and less fat oxidation, indi-
cated by a rise in the RER. Although there are ergo-
genic benefits from creatine supplementation, athletes
participating in wrestling, swimming, gymnastics, and
other weight-sensitive sports should first consider the
Fig. 2. Percent participation of a substrate in total energy utiliza- potentially negative side effect of fat retention before
tion. *P ⬍ 0.05, precreatine vs. postcreatine carbohydrate. choosing creatine supplementation.
J Appl Physiol • VOL 93 • DECEMBER 2002 • www.jap.org2022 CREATINE SUPPLEMENTATION AFFECTS SUBSTRATE UTILIZATION
The authors thank J. Thwaits and S. Ball for their time and suring human body composition. Med Sci Sports Exerc 27: 1686–
assistance. 1691, 1995.
13. McCrory MA, Mole PA, Gomez TD, Dewey KG, and Ber-
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