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Creatine and b-Hydroxy-b-Methylbutyrate (HMB)
Additively Increase Lean Body Mass and Muscle
Strength During a Weight-Training Program
Ewa Jo´wko, MS, Piotr Ostaszewski, DVM, PhD, Michal Jank, DVM, Jaroslaw Sacharuk, PhD,
Agnieszka Zieniewicz, MS, Jacek Wilczak, PhD, and Steve Nissen, DVM, PhD
From the Institute of Sport and Physical Education, Biala Podlaska, Academy of Physical
Education, Warsaw, Poland; the Department of Physiology, Biochemistry, Pharmacology
and Toxicology and the Department of Human Nutrition and Home Economics,
Warsaw Agricultural University, Warsaw, Poland; and the Iowa State University,
Ames, Iowa, USA
We investigated whether creatine (CR) and b-hydroxy-b-methylbutyrate (HMB) act by similar or
different mechanisms to increase lean body mass (LBM) and strength in humans undergoing progressive
resistance-exercise training. In this double-blind, 3-wk study, subjects (n 5 40) were randomized to
placebo (PL; n 5 10), CR (20.0 g of CR/d for 7 d followed by 10.0 g of CR/d for 14 d; n 5 11), HMB
(3.0 g of HMB/d; n 5 9), or CR-and-HMB (CR/HMB; n 5 10) treatment groups. Over 3 wk, all subjects
gained LBM, which was assessed by bioelectrical impedance analysis. The CR, HMB and CR/HMB
groups gained 0.92, 0.39, and 1.54 kg of LBM, respectively, over the placebo group, with a significant
effect with CR supplementation (main effect P 5 0.05) and a trend with HMB supplementation (main
effect P 5 0.08). These effects were additive because there was no interaction between CR and HMB
(CR 3 HMB main effect P 5 0.73). Across all exercises, HMB, CR, and CR/HMB supplementation
caused accumulative strength increases of 37.5, 39.1, and 51.9 kg, respectively, above the placebo group.
The exercise-induced rise in serum creatine phosphokinase was markedly suppressed with HMB supplementation
(main effect P 5 0.01). However, CR supplementation antagonized the HMB effects on serum
creatine phosphokinase (CR 3 HMB interactive effect P 5 0.04). Urine urea nitrogen and plasma urea
were not affected by CR supplementation, but both decreased with HMB supplementation (HMB effect
P , 0.05), suggesting a nitrogen-sparing effect. In summary, CR and HMB can increase LBM and
strength, and the effects are additive. Although not definitive, these results suggest that CR and HMB act
by different mechanisms. Nutrition 2001;17:558 –566. ©Elsevier Science Inc. 2001
KEY WORDS: body composition, bioelectrical impedance, creatine, creatine phosphokinase, b-hydroxyb-
methylbutyrate, leucine, muscle
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Creatine (CR) and b-hydroxy-b-methylbutyrate (HMB) are supplements
used to enhance the effects of weight training on muscle
mass. Although several mechanistic explanations have been offered
to show how these compounds enhance exercise-responsive
muscle growth, to date there has been no experimental evidence
showing whether any of these hypotheses are valid. One approach
to this problem is to determine whether the effects of HMB and CR
are independent. Additivity of those effects would support distinct
mechanisms of action, and lack of additivity would support a
common mechanism. Thus, we investigated whether HMB and CR
were additive in relation to lean body mass (LBM) and strength
gains and whether these indicated independent mechanisms.
CR supplementation has been shown to raise muscle CR concentrations
by approximately 15%,1–9 and that rise has been associated
with increased LBM and strength.1,5,10,11 It has been postulated
that the increase in muscle CR increases LBM by
osmotically drawing more water into the muscle cell.1,4,10,11 This
cellular swelling would then stimulate protein synthesis in the
muscle cells.1 As yet there have been no studies directly measuring
muscle-cell water changes in humans. In addition, in vitro studies
have suggested that CR can increase myosin synthesis but does not
affect total protein synthesis.12–14
The leucine metabolite, HMB, also has been shown to increase
LBM and strength in exercising humans.10,15–17 Two mechanisms
for HMB action have been proposed. The first is based on the
observation that HMB can slow or suppress muscle proteolysis
that is elevated during exercise.15,17 The second possible mechanism
concerns HMB being a precursor of muscle-cell cholesterol.
The increase in muscle hypertrophy during weight training might
result in a local deficiency in cholesterol in the muscle cell, which
might result in inadequate cholesterol for membrane synthesis and
thus slower cell growth or suboptimally functioning cell membranes
due to a shortage of membrane cholesterol. Suppling critical
amounts of cholesterol precursor in muscle would allow the
muscle to maintain and synthesize new muscle plasma membranes.
This idea is supported by observations showing that muscle-membrane damage (leakage) was markedly decreased when HMB
was supplemented in the diet.15–18
Proposed mechanisms for CR and HMB action are clearly
speculative at this time. However, if it can be shown that the effects
of HMB and CR are additive relative to LBM increase, this would
provide preliminary evidence consistant with the proposed mechanisms
of action. Conversely, if the effects of HMB and CR are not
additive, then one of the two proposed mechanisms would be
wrong. We also examined several metabolic markers of cell metabolism,
nitrogen metabolism, and strength to support the LBM
gain data. Together these data should establish similarities or
differences between CR and HMB mechanisms of action.

Subjects
Forty healthy male subjects 19 to 23 y old were enrolled into the
study. All had been involved in prior exercise but none were highly
trained. Potential subjects were excluded from the study if they had
evidence or history of any disease, recent joint or bone injury, or
obesity. Subjects also were excluded if they had participated in
resistance-exercise programs in the previous 6 mo or had consumed
HMB or CR in the previous 3 mo before the study. All
subjects were screened by blood analysis, urinalysis, physical
examination, and body composition. The study was approved by
the Ethical Committee of the Academy of Physical Education in
Warsaw, and informed written consent was

Progressive Weight-Training Regimen
Each subject was tested for a one-repetition maximum (1-RM)
before the study in all of the exercises except the sit-up crunch.
The number of lifts was minimized during testing so as not to
constitute a training effect. Weight training continued three times
per week throughout the study with at least 1 d of rest between
sessions. The strength-training program consisted of concentric
and eccentric isotonic lifting exercises that worked each muscle
group with free weights. The selection of exercises was based onthe training program for beginners; the seven exercises were
chosen to involve the main large muscle groups as follows: chest,
upper back, shoulders, arms, abdominal, and legs. The training
program used is shown in Table II.
The initial weight lifted was calculated by using 1-RM as
100%. The training weight was then estimated at the level at which
the subject could make 5 to 15 repetitions before failure. The
weight lifted was increased slowly to keep the number of repetitions
and sets the same. For example, if the subject easily completed
or exceeded the planned number of repetitions in the last set,
then the following calculation was used to estimate an increase in
weight to be lifted during the next session. The number of planned
repetitions was subtracted from the number of completed repetitions
and divided by two. The value obtained was the number of
kilograms, which were then added to the existing weight to have
the target weight to be lifted at the next session. Each session was
monitored by trained supervisors who recorded the weights lifted
and repetitions performed.

DISCUSSION
The major finding of this research was that supplementation with
CR and HMB was additive with regard to increasing LBM and
strength. These observations are consistent with, but do not prove,
the hypothesis that CR and HMB act through distinct mechanisms.
HMB had an acute effect on LBM that was about half the
magnitude of CR. The increase in LBM in the CR/HMB group was
higher than that in the CR and HMB groups (2.39 kg versus 1.77
kg and 1.24 kg, respectively). The increases due to CR and HMB
supplementation were additive because there was no significant
interaction (Fig. 1a).
The strength increase in the CR/HMB group also was shown to
be additive (CR 3 HMB effect P 5 0.10), thus supporting the
concept that CR and HMB have different mechanisms of increasing
strength (Fig. 1b). Greater strength according to the benchpress
and triceps-extension exercises was observed in the placebo
group at screening and appeared to be a random-chance occurrence
because the other strength measurements were not significantly
higher in the placebo group than in the other groups.
The mechanism whereby HMB increases LBM and strength is
proposed to be through a net increase in muscle-protein synthesis
brought about by a decrease in protein degradation. Although not
directly related to muscle-protein turnover, previous studies have
shown that reduced protein degradation is accompanied by a lower
serum-CPK level, CPK being an indicator of muscle-cell membrane
damage.15–17 In this study, there was a significantly lower
increase in serum CPK in week 2 with HMB supplementation
(HMB effect P 5 0.01) and a numerically lower week-3 serum-
CPK concentration (HMB effect P 5 0.21) in comparison with thenon–HMB-supplemented groups. In addition, the 42% decrease in
urinary urea nitrogen and 26% decrease in serum urea nitrogen
with HMB supplementation (Fig. 3) supports the idea of increased
net-protein deposition.
CR supplementation has been proposed to increase LBM by
increasing osmotic pressure in muscle, which increases the water
content of the muscle.1,4,10,11 In this study, a significant increase in
BCM, TBW, and ICW was shown in all groups supplemented with
CR. There also were similarities in all groups between the percentage
of LBM gain and percentage of BCM, TBW, and ICW
increases. In vitro studies have shown that the rate of [3H]leucine
incorporation into heavy-chain myosin increases in skeletal and
cardiac muscles with exposure to CR but that total protein synthesis
does not change.12–14 The increase in muscle strength and LBM
that occurred with CR supplementation in this study may have
been due to this specific increase in muscle-protein synthesis. The
urine-urea data (Table VI) suggest that CR supplementation did
not affect nitrogen retention. However, urine urea nitrogen alone
can be difficult to interpret because of relative nitrogen shifts when
separating urea from ammonia, which can result in changes in
urine urea without changes in total nitrogen output. However, CR
metabolism is not known to affect the shift between urea and
ammonia, so it is unlikely that CR caused a net increase of nitrogen
and most unlikely that it affected net-protein synthesis.
Serum creatinine concentration increased by about 17% in
week 2 in the CR-supplemented groups and remained elevated for
the length of the study. Creatinine has been established as the sole
end product of CR degradation because it is formed nonenzymatically
in an irreversible chemical reaction.2,23 The raised
serum creatinine results from increased muscular CR. Urinary
creatinine increased in the CR-supplemented groups in week 2 as
a result of increased serum creatinine.
CR alone had no effect on CPK levels and seemed to reverse
the protective effect of HMB to about one-half of HMB alone (Fig.
2). This loss of HMB’s ability to protect against the exerciseinduced
rise in CPK when combined with CR could be the result
of mechanisms different from those hypothesized for CR and
HMB.
Dietary analysis of the different groups indicated that the CR
groups had lower caloric intakes of 13% to 20% in week 2 and 7%
to 10% in week 3 in comparison with the placebo and HMB
groups. Although a lower caloric intake should result in a negative
energy balance, fat mass was actually increased in the CRsupplemented
groups compared with the placebo and HMBsupplemented
groups. Protein intake was also 6% to 14% lower in
the CR groups than the placebo and HMB groups in week 3.
However, total protein intake in all groups was approximately
180% of the recommended daily allowance, suggesting that the
slightly lower protein intake was still well above that required.
In conclusion, we found that HMB and CR increase LBM and
strength in an additive manner during a progressive resistancetraining
regimen. Although the present data did not determine the
exact mechanisms of CR and HMB action, they are consistant with
previously theoreticized mechanisms, i.e., that HMB increases
LBM by slowing muscle-protein breakdown, whereas CR increases
LBM by increasing cellular water content.