© Freund Publishing House Ltd.

, London Journal of Pediatric Endocrinology & Metabolism, 23,641-650 (2010)

Effect of HMB Supplementation on Body Composition, Fitness,

Hormonal Profile and Muscle Damage Indices
Shawn Portal1'4, Alon Eliakim2, Dan Nemet2, Orna Halevy3, Zvi Zadik4'5
l
Ribstein Center for Sport Medicine Sciences and Research, Wingate Institute, Netanya, 2Child Health
and Sports Center, Dept. of Pediatrics, Meir Hospital, Kfar-Saba, Sackler School of Medicine, Tel Aviv
University3Dept. of Animal Sciences, *School of Nutritional Sciences, both of The Hebrew University of
Jerusalem, Rehovot,''Research Authority, Kaplan Medical Center, Rehovot, Israel

ABSTRACT KEY WORDS

There is a huge market for ergogenic ergogenic supplement, nutritional supplement, ß-

supplements for athletes. However, only a few
products have been proven to have ergogenic
effects and to be effective at improving muscle
strength and body composition. One such
supplement is ß-hydroxy ß-methylbutyrate
(HMB). Derived from the amino acid leucine
and its keto acid -ketoisocaproate (KIC),
HMB has been well documented as an oral
ergogenic supplement commonly used by
athletes. Several studies have shown that
combining exercise training with HMB
supplementation leads to increased muscle
mass and strength, and there is some anecdotal
evidence of aerobic improvement. However,
HMB supplementation has been found to be
effective mainly for untrained individuals.
While previous reviews have emphasized three
main pathways for HMB's mode of action: 1)
enhancement of sarcolemmal integrity via
cytosolic cholesterol, 2) inhibition of protein
degradation via proteasomes, and 3) increased
protein synthesis via the mTOR pathway,
more recent studies have suggested additional
possible mechanisms for its physiological
effects. These include decreased cell apoptosis
and enhanced cell survival, increased
proliferation, differentiation and fusion via the
MAPK/ERK and PI3K/Akt pathways, and
enhanced IGF-I transcription. These are
described here, and hormonal interactions are
discussed, along with HMB dosage and safety
issues.
Corresponding author:
Shawn Portal
shawn@holmesplace.co.il
hydroxy ß-methylbutyrate, HMB, IGF, fitness,
muscle damage, muscle anabolism, adolescent
athlete
NUTRITIONAL SUPPLEMENTS AND
PHYSICAL PERFORMANCE
The ergogenic supplement industry earns huge
sums selling nutritional supplements that
purportedly enhance physical performance, defer
fatigue and improve body composition and
appearance. In the achievement-oriented world of
sports, where the difference between fame and
shame is measured in microseconds or milli-
meters, the slightest improvement may be
significant for the competitive athlete1. However,
a meta analysis examining tens of supplements2
found only a few with proven ergogenic effects.
Another overview3 found that only a handful of
supplements had been proven effective for
improvement of muscle strength and body com-
position (e.g. creatine monohydrate).
The popularity of supplement use among
adolescents in general and adolescent athletes in
particular is on the rise, even though very little is
known about their safety or efficacy4"7. A study
examining the extent of use of nutritional
supplements among young volleyball and soccer
players found that 8% of the boys and 2% of the
girls use ergogenic nutritional supplements to
improve exercise performance and body com-
position8. It is surprising that despite the
widespread use of these supplements, only 14%
of all users consult with health professionals

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642 S. PORTAL ET AL
before using them9. In recent years, -hydroxy -
methylbutyrate (HMB) has become one of the
most popular supplements among those training
in workout gyms, young people among them9.
HMB
The anti-catabolic effects of the amino acid
leucine10 and its metabolites, such as a-
ketoisocaproate (KIC), have been well known for
years11. A few drops of leucine appear to assist in
reducing loss of nitrogen and protein by delaying
the latter's degradation and decomposition12. In
mitochondria, KIC is metabolized to isovaleryl-
CoA through the enzyme ketoacid dehydro-
genase, whereas in the cytosol it metabolizes to
HMB, which is thought to delay protein
decomposition mediated by KIC dioxygenase12.
Most of the KIC is converted to isovaleryl-CoA
and under normal circumstances; about 5% of the
leucine is metabolized to HMB13.
Studies of leucine and KIC supplementation in
vitro (for humans and animals) have shown an
anabolic effect only in catabolic states in which
increased proteolysis occurs, such as starvation or
serious burns14'17. This implies that the anti-
catabolic/anabolic activity of leucine and its
metabolites may be effective during a training
period characterized by high physical stress and
catabolic processes18.
About 60 g of leucine are needed to produce
3 g of endogenic HMB (which is the recom-
mended dose in most cases)1 . Daily endogenic
synthesis of HMB is 0.3 to 1.0 g, and depends
upon the quantity of HMB received from foods
such as grapefruit, certain fish and meat, as well
as dairy products.
Several papers have been published in recent
years about the reducing effects of HMB on
catabolic processes.Scares et α/20 showed that
giving HMB while simultaneously preventing
hind leg movement in rats reduces muscle
damage and assists in enlarging the diameter of
the muscle fibers. Rathmatcher et α/.21 showed
that giving HMB to bedridden patients reduces
the extent of muscle atrophy.
A few clinical studies have shown that HMB
may contribute to a reduction in muscle mass loss
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in diseases characterized by catabolic processes,
such as AIDS22'23 or malignancies24, and also to a
reduction in sarcopenia and a slowing of the
biological decrease in muscle strength in the
elderly25"28. The effects of HMB on changes in
body composition were also examined in negative
caloric balance29, and findings showed less lean
body mass (LBM) wasting during HMB
supplementation.
Most studies examining the effects of HMB
on preventing catabolic processes have been
undertaken with a sport-oriented ergogenic
orientation. The rational for examining the impact
of HMB on effectiveness of physical performance
in athletes is the fact that HMB has the ability to
reduce protein degradation during intense periods
of training30.
IMPACT OF HMB ON PHYSICAL PERFORMANCE
AND BODY COMPOSITION
HMB is widely used as an ergogenic
supplement, mainly among bodybuilders and
power athletes who are seeking to improve
performance or enlarge muscle mass31. In an
overview of nutritional supplements in which
they were categorized according to safety and
effectiveness, HMB was rated in the first of four
categories, together with creatine2. However, the
authors noted that its main ergogenic impact was
seen mostly in untrained subjects: for experienced
athletes, HMB was rated only second out the four
categories.
As noted, HMB is an anti-catabolic agent that
contributes to reduction in muscle damage caused
by strength training18. That study found that daily
supplementation of 3 g IIMB for 3 weeks in
parallel to strength training sessions leads to
significant improvements in strength (18.4%),
relative to 1.5 g/day (13%) or a placebo (8%),
among 41 young adults (ages 22-29) who were
not used to performing strength training.
Significant improvement in quadriceps
strength was also found among 34 trained men
supplemented with 3 g HMB daily together with
strength training for 9 weeks32. Gallagher et α/.33
examined the effects of various dosages of HMB
(0, 3 or 6 g/day) on 37 untrained college students
 ERGOGENIC EFFECTS OF ß-HYDROXY ß-METHYLBUTYRATE (HMB)
who trained for 8 weeks, three sessions per week,
each session including 10 different strength
exercises at an intensity of 80% of 1RM (one
repetition maximum). Results showed that,
despite a lack of significant difference in the
enhancement of maximum strength (1RM) be-
tween groups, a significant increase in isometric
and isokinetic strength, in addition to an increase
in LBM, was found in the HMB group. No
differences were found between daily dosages of
3 or 6 g. In another double-blind controlled study,
it was found that supplementing HMB for 9
weeks in trained subjects causes increased muscle
strength but no change in body composition32. An
increase in LBM and a reduction in body fat
percentages were found in another double-blind
controlled study which examined senior subjects
(70 ± 1 years of age; 15 men, 16 women) who
were subjected to five weekly training sessions
for 8 weeks and took 3 g HMB/day34.
In their review of studies examining the
effects of HMB for periods of over 3 weeks, with
at least two to three strength-training sessions per
week, Steven et al? showed that supplementing
with HMB causes significant enhancement in
muscle strength (1.40% per week) and in LBM
(0.28% per week). It should be noted, however,
that some of these studies were financed by
supplement manufacturers, and more studies
funded by neutral sources are warranted.
Most of the studies examining the effect of
HMB supplementation on physical performance
have been performed in the area of strength
training: only a few have examined the con-
tribution of HMB to enhancement of aerobic
capacity and stamina performance. In one of
these, it was found that HMB supplementation
causes longer riding times to exhaustion in a
graded cycle ergometer test: eight well-trained
cyclists (training volume of 300 miles per week)
were examined over periods of 2 weeks. The
effects of HMB supplementation were analyzed
on oxygen consumption (VO2) measured at a
level of exertion which produced 2 mM lactate,
and compared to effects of an identical dosage of
leucine (3 g/day) or a placebo34. The time taken
to reach an acidity level of 2 mM was longer for
the HMB group than for the leucine or placebo
groups, which did not differ. In addition, oxygen
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643
consumption was greater at this level of acidity in
the HMB group. While the maximum con-
centrations of lactate did not change, a greater
rise was seen in the lactic acid threshold after
taking HMB (9.1 ± 2.4%) and leucine (2.1 ±
1.5%) as compared to the placebo (0.75 ± 2.1%).
These findings suggested that HMB may also
contribute to enhancement of endurance perform-
ance. The hypothesis was that the contribution of
HMB to aerobic capability may be explained by
its contribution to size and density of the
mitochondria responsible for oxygen oxidation,
and that the improvement in aerobic capability
leads to disposal of lactic acid.
These findings were corroborated in a recent
study35 in which active students were required to
perform three interval-training sessions a week
for 5 weeks. A significant improvement in
maximal oxygen consumption was found in the
HMB group (13.4%) compared to the control
group (8.4%). In contrast, rugby players who
supplemented for 6 weeks showed no improve-
ment in performance, as measured by the graded
exertion test36.
Kreider et al. published a review on
supplements which concluded that the efficacy of
HMB had been proven mainly for untrained
subjects, and it was less consistent with trained
athletes. A few years later, Wilson et al}9
published a review which concluded that the main
reasons for that discrepancy were related to
methodology failure in some studies, for ex-
ample, nonspecific tests used to evaluate
improvement in a particular sport (e.g., rugby
players tested on 60-s maximal test36), and to
inadequate time periods allowed for adaptation to
HMB supplementation (e.g., a 10-day training
camp37). A more recent study38 showed signi-
ficant improvement in strength but not in body
composition after 9 weeks of HMB supple-
mentation in resistance-trained men.
HMB'S ANTI-CATABOLIC EFFECT AND
REDUCTION IN MUSCLE DAMAGE
Increasing training load is liable to cause
muscle damage by creating micro-trauma to
muscle fibers and connective tissues. Muscle
644 S. PORTAL ET AL
damage increases in correlation to training load,
and the athlete requires a longer recovery time
before he/she can increase training load in order to
further improve physical ability. The demanding
training program of competitive sports often does
not allow full recovery between training sessions
or competitions and as a result, catabolic
processes in the muscle increase39. This raises the
need for means of shortening recovery times
between training sessions and/or reducing the
damage during training. It has been found that
intense activity for short periods intensifies the
muscle pains that occur 8 to 48 h after training, as
opposed to training at low intensity for longer
times39, Therefore, the phenomenon may be more
widespread in power sports and ball sports
(including volleyball, basketball and soccer).
Muscle pain is one measure of the amount of
muscle damage, but because pain reports are
subjective, the accepted method is to track levels
of the muscle enzymes creatine kinase (CPK) and
lactate dehydrogenase (LDIi) in the serum.
Concentrations of these enzymes are proportional
to processes of energy production in the anaerobic
pathway in muscle cells: damage to the muscle
cell membrane causes them to seep out of the cell
and raises their concentrations in the serum.
Despite the fact that several studies have
demonstrated reductions in serum CPK levels
after taking 3g of HMB while performing strength
training18 or aerobic training40, a recent study41
showed no benefit at all from taking HMB before
and after exertion in an attempt to reduce muscle
damage. In addition, a recently published meta
analysis42 determined that HMB has only a minor,
if any, effect in preventing the rise in CPK.
THEORETICAL MECHANISMS OF ACTION
OF HMB
1. A Component in Muscle Cell Membranes
Cholesterol is an integral part of the cell
membrane and is vital to the integrity of the cell
wall, as well as for regulation of intracellular
processes. Improved regenerative capability of the
cell wall may reduce damage to internal cell
processes that depend upon this integrity. This
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process is of particular significance in muscle
tissue because of its dependence on the de novo
production of cholesterol. Support for this
hypothesis, termed the "Cholesterol Synthesis
Theory" for Enhanced Membrane Function18, is
found in research showing that delay of
cholesterol synthesis impairs muscle function43,
leads to increased muscle damage44, and finally
also to necrosis45. Cholesterol is produced from
acetyl-CoA with the rate-limiting step being
synthesis of mevalonic acid, which is a precursor
to cholesterol in the cytosol of muscle (and liver)
cells. This process is mediated by the enzyme
HMG (hydroxy-methyl-glutaryl)-CoA reductase.
Most of the HMB is converted to HMG-CoA,
which turns into cholesterol4 . Damaged muscle
cells lack the ability to produce the amounts of
cholesterol needed to stabilize the sarcolemma.
HMB supplementation may be effective in
reconstructing and repairing the cell wall that is
damaged during performance of physical exertion,
thereby preventing leakage of muscle enzymes
such as CPK from the cell.
In addition, there is evidence suggesting that
HMB itself is covalently connected to several
structures in the tissue18. Tissue hydrolysis in the
presence of acid-alkali showed HMB con-
centrations of between 10 and 100 μΜ13. These
findings suggested that HMB is a component of
the cell membrane or other cell structures, thereby
providing a possible explanation for its function in
preserving muscle tissue.
2. Inhibition of Apoptosis and Proteolytic Pathways
Previous studies have shown that incubation of
muscle tissue with leucine or KIC reduces muscle
damage47. This claim is supported by the fact that
concentrations of essential amino acids in the
bloodstream during fasting (originating mainly in
spontaneous muscle breakdown) are reduced after
supplementation with HMB. In addition, the
reduced concentration of enzymatic muscle-
damage markers might indicate that the main
effect occurs via reductions in muscle damage and
inflammation18.
A study performed by Smith et α/.48 has
suggested that HMB attenuates protein
degradation via inhibition of the ubiquitin-
 ERGOGENIC EFFECTS OF -HYDROXY -METHYLBUTYRATE (HMB)
proteasomc proteolytic pathway in muscle cells.
Ubiquitin activity is induced by certain agents and
catabolic conditions, including gluco-
corticosteroids, cytokines, hunger, oxygen stress
(exertion), activity reduction, and immobilization.
Those factors are thought to induce proteasome
expression through activation of the transcription
factor nuclear factor kappa B (NF-κΒ) and
accelerate muscle wasting49. HMB supple-
mentation has been found to suppress the activity
of NF-κΒ and to lead to retention of muscle mass
and prevention of muscle degeneration and
atrophy in vitro.
Recently, Eley et al.50 showed attenuation of
protein degradation mediated by both tumor
necrosis factor-α (TNF-α) and angiotensin II
(ANG II) after treatment with HMB in murine
myotubes. The signaling pathway involves the
initial activation of caspases 3 and 8, followed by
autophosphorylation and activation of Protein
kinase R (PKR), which then leads to increased
reactive oxygen species (ROS) formation via
activation of p38 mitogen-activated protein kinase
(p38 MAPK). Increased ROS formation is known
to increase NF-κΒ activity, which induces protein
degradation through the ubiquitin-proteasome
pathway. These findings were recently
substantiated by Russell and Tisdale5 .
Phosphorylation of PKR also activates the
elongation factor eIF2a, which in turn reduces
translational efficiency and leads to decreased
protein synthesis (data not shown)50.
The activation of caspases by either TNF-α or
ANG II, or by other traumas (e.g., hypoxia)
during muscle aging and degenerative myopathies
leads to apoptosis and depletion of the muscle
progenitor satellite cells52' 3. A recent study has
shown a reduction in the number of apoptotic
myoblasts derived from satellite cells in the
presence of HMB as reflected by a reduction in
the number of pycnotic nuclei, as well as higher
levels of the anti-apoptotic proteins Bcl-2 and Bcl-
X, and lower levels of the pro-apoptotic protein
ΒΑΧ54. The anti-apoptotic proteins sequester the
pro-apoptotic ones, thereby preventing
permeabilization of the outer mitochondria!
membrane and subsequent activation of
downstream caspases. These findings suggest that
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645
HMB plays a role in preventing apoptosis and
protein degradation, thereby enhancing the
survival of satellite cells which are crucial for
muscle regeneration and inhibition of muscle
wasting.
3. Enhanced Protein Synthesis, Cell Proliferation
and Differentiation
As muscle mass is a reflection of the balance
between protein degradation and synthesis, studies
have been conducted to identify anabolic
pathways to which HMB might be related. Smith
et al.55 demonstrated that HMB supplementation
in a model of cancerous rats leads to increased
muscle mass. This was supported by Eley et al.5
who showed that HMB stimulates protein
synthesis by increasing phosphorylation of the
mammalian target of rapamycin (mTOR), a
protein kinase that lies downstream of the
phosphoinositide-3 kinase (PI3K)/Akt pathway
which upregulates protein synthesis at the level of
translation initiation57.
Providing another line of evidence for the
anabolic actions of HMB on muscle, Kornasio et
α/.54 reported that HMB promotes myogenic cell
proliferation, differentiation and accelerated
fusion, as shown by the induction of muscle
proliferation and differentiation-specific markers.
Moreover, HMB increased the mRNA levels of
insulin-like growth factor I (IGF-I), which is
known to play a pivotal role during myoblast
proliferation and differentiation and muscle
hypertrophy58·60. These effects of HMB were
mediated by the MAPK/ERK and PI3K/Akt
pathways, leading the authors to conclude that the
direct effects of HMB on myoblast differentiation
resemble those of IGF-I, at least in culture. HMB's
mechanisms of action are summarized in Fig 1.
Hormonal and Anti-Inflammatory Effects of
HMB
The belief that HMB affects anabolic and
catabolic processes leads to the notion that
anabolic and catabolic hormones, growth factors
(e.g., IGF-I) and inflammatory mediators might
play a role in HMB's exercise-induced effects.
646 S. PORTALETAL

HMB

HMGCoA
,7
l
Cspase8

Cell
I Caspase3
membrane
Integrity I
NF-kB
( Protein \
Synthesis/

I
Proteasome +E3mRNA
I IGF-l mRNA

Inhibition of Inhibition of
apoptosls cachexla PHYSIOLOGICAL
^. . . . .~~-.·η||- ., ...η ...&

Dlfleretn
EFFECTS

Fig. 1: HMB's mechanism of action: 1) Enhancement of sarcolemmal integrity via cytosotic cholesterol. 2) Inhibition of
protein degradation via proteasome decreasing cell apoptosis and leading to enhanced cell survival. 3) Increased
protein synthesis via mTOR pathway. 4) Increased proliferation, differentiation and fusion via the MAPK/ERK and
P13K/Akt pathways and enhanced IGF-1 transcription.

Previous studies in children and adolescents Interestingly, however, very few studies have
have shown that sudden imposition of a training examined the relationship between exercise,
program which is associated with a substantial HMB supplementation, and changes in anabolic-
increase in energy expenditure initially leads to /catabolic hormones and inflammatory mediators.
an increase in proinflammatory cytokines, and as Previous studies have shown that HMB has no
a consequence, to a decrease in IGF-I levels. If influence on testosterone/ epitestosterone level. In
training is accompanied by inadequate nutrition, contrast, young sheep that were supplemented
and negative energy balance is sustained for with HMB demonstrated an increase in GH and
prolonged periods, overall growth might be IGF-I levels, accompanied by an increase in
attenuated. However, if the training adaptation is muscle strength and bone mass62. IGF-I elevated
successful and a new steady state is achieved, the levels could be due to the increased GH levels but
level of proinflammatory cytokines falls. Con- also could be the isoform secreted by myogenic
comitantly, the suppression of IGF-I is alleviated cells59'60 as was recently shown54. In humans,
and an anabolic "rebound" in the Gil (growth studies have demonstrated that HMB supp-
hormone)-IGF-I axis may ensue, causing IGF-I lementation causes a reduction in inflammatory
levels to exceed the pretraining level. Exactly indices [c-reactive protein (CRP)] in chronic
how and when this switch takes place, and obstructive pulmonary disease (COPD) patients
whether the initial catabolic-type stage is hospitalized in the ICU63, whereas no effect was
necessary for the ultimate anabolic adaptation found for short-term (10 days) HMB supp-
remain unknown61. lementation in young football players on levels of

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 ERGOGENIC EFFECTS OF ß-HYDROXY ß-METHYLBUTYRATE (HMB)
testosterone and cortisol, known as reflectors of
athletes' anabolic and catabolic status37. However,
the efficacy of the supplement needs to be studied
under longer term use.
USE OF HMB
1. Dosage
Most studies recommend supplementing 3 g
HMB/day (divided into two or three doses): lower
doses of HMB have been found to be less
effective, whereas higher doses have demon-
strated no additional benefit.
2. Safety
A number of studies have examined the extent
to which use of HMB as a supplement is safe33.
No changes were found in the levels of glucose,
urea or hemoglobin, in liver functions or in white
blood cell profiles among 37 college students
consuming HMB at doses of 3 or 6 g daily for 8
weeks and performing resistance strength training
3 days a week. Nissen et al64 examined tolerance
and side effects in an overview of nine different
studies in which subjects were supplemented with
3 g HMB/day. The subjects included women and
men, youth and adults, trained and untrained. The
results showed a reduction in general cholesterol
level (5.8%, p < 0.03) and LDL cholesterol (7.3%,
p < 0.01) (only for subjects with hyper-
cholesterolemia), and a lowering of systolic blood
pressure (4.4 mm Hg, p < 0.05) with supple-
mentation. The mechanism underlying the
lowering of cholesterol was not found, although
the supplement used in the study was comprised
of calcium in quantities of 300 to 600 mg bound
to the HMB, and this apparently contributed to the
reduction in endogenous cholesterol concentration
by increasing the secretion of bile salts65. Health
aspects aside, the guidelines of the International
Olympic Committee for the prevention of sports
drugs do not permit athletes to consume a number
of different types of organic substances. For this
reason, the effect of HMB supplements on
epitestosterone-to-testosterone ratio was examined
(a ratio higher than 1:6 disqualifies the athlete).
The supplement was not found to have any effect
on this ratio30.
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647
CONCLUSIONS
HMB supplementation has been associated
with a significant increase in muscle mass and
strength, and might support aerobic capabilities
with little or no effect on muscle damage. The
beneficial effects of HMB occur primarily in
untrained individuals or in trained subjects who
are in the initial phases of training.
Further research is needed to determine the
effects of HMB over longer periods of use or in
other segments of the training season (for
instance, periods of competition or specific
preparatory periods characterized by other training
components, such as more significant aerobic or
break-through strength training) to clarify the
efficacy of the supplement, specifically in highly
trained athletes. An examination of HMB's
effectiveness in other areas of sports is also
warranted. In addition, research is needed to
determine whether the effects of HMB are
reduced or annulled in the presence of positive
caloric and nitrogen balances.
Finally, most of the studies on HMB
supplementation have demonstrated its beneficial
effects in adults. However, its effects are par-
ticularly important in childhood and puberty, since
during this period there is a spontaneous increase
in anabolic hormones that leads to a marked
puberty-related growth spurt and increase in
muscle mass. It is certainly not clear that any
anabolic supplementation will have additional
beneficial effects during periods of spontaneous
anabolic spurts. Moreover, any HMB-training-
associated body composition, hormonal and/or
inflammatory effect during this critical period
could potentially have profound consequences on
overall growth and development, especially if the
effect is maintained for long periods. Thus, future
studies on HMB's effects in the child and
adolescent athlete are mandatory.
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