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Effects of beta-hydroxy-beta-methylbutyrate (HMB) on exercise performance and body composition across varying levels of age, sex, and training experience: A review

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The leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) has been extensively used as an ergogenic aid; particularly among bodybuilders and strength/power athletes, who use it to promote exercise performance and skeletal muscle hypertrophy. While numerous studies have supported the efficacy of HMB in exercise and clinical conditions, there have been a number of conflicting results. Therefore, the first purpose of this paper will be to provide an in depth and objective analysis of HMB research. Special care is taken to present critical details of each study in an attempt to both examine the effectiveness of HMB as well as explain possible reasons for conflicting results seen in the literature. Within this analysis, moderator variables such as age, training experience, various states of muscle catabolism, and optimal dosages of HMB are discussed. The validity of dependent measurements, clustering of data, and a conflict of interest bias will also be analyzed. A second purpose of this paper is to provide a comprehensive discussion on possible mechanisms, which HMB may operate through. Currently, the most readily discussed mechanism has been attributed to HMB as a precursor to the rate limiting enzyme to cholesterol synthesis HMG-coenzyme A reductase. However, an increase in research has been directed towards possible proteolytic pathways HMB may operate through. Evidence from cachectic cancer studies suggests that HMB may inhibit the ubiquitin-proteasome proteolytic pathway responsible for the specific degradation of intracellular proteins. HMB may also directly stimulate protein synthesis, through an mTOR dependent mechanism. Finally, special care has been taken to provide future research implications.
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BioMed Central
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Nutrition & Metabolism
Open Access
Review
Effects of beta-hydroxy-beta-methylbutyrate (HMB) on exercise
performance and body composition across varying levels of age, sex,
and training experience: A review
Gabriel J Wilson*
1
, Jacob M Wilson
2
and Anssi H Manninen
3
Address:
1
Division of Nutritional Sciences, University of Illinois, Urbana, Illinois, USA,
2
Department of Nutrition, Food and Exercise Science,
Florida State University, Tallahassee, Florida, USA and
3
Manninen Nutraceuticals Oy, Oulu, Finland
Email: Gabriel J Wilson* - gwilson@abcbodybuilding.com; Jacob M Wilson - jmw06x@fsu.edu;
Anssi H Manninen - anssi.manninen@gmail.com
* Corresponding author
Abstract
The leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) has been extensively used as an
ergogenic aid; particularly among bodybuilders and strength/power athletes, who use it to promote
exercise performance and skeletal muscle hypertrophy. While numerous studies have supported
the efficacy of HMB in exercise and clinical conditions, there have been a number of conflicting
results. Therefore, the first purpose of this paper will be to provide an in depth and objective
analysis of HMB research. Special care is taken to present critical details of each study in an attempt
to both examine the effectiveness of HMB as well as explain possible reasons for conflicting results
seen in the literature. Within this analysis, moderator variables such as age, training experience,
various states of muscle catabolism, and optimal dosages of HMB are discussed. The validity of
dependent measurements, clustering of data, and a conflict of interest bias will also be analyzed. A
second purpose of this paper is to provide a comprehensive discussion on possible mechanisms,
which HMB may operate through. Currently, the most readily discussed mechanism has been
attributed to HMB as a precursor to the rate limiting enzyme to cholesterol synthesis HMG-
coenzyme A reductase. However, an increase in research has been directed towards possible
proteolytic pathways HMB may operate through. Evidence from cachectic cancer studies suggests
that HMB may inhibit the ubiquitin-proteasome proteolytic pathway responsible for the specific
degradation of intracellular proteins. HMB may also directly stimulate protein synthesis, through
an mTOR dependent mechanism. Finally, special care has been taken to provide future research
implications.
Introduction
The branched chain amino acids (BCAAs) leucine, isoleu-
cine, and valine make up more than one third of muscle
protein [1]. Of these, the most investigated BCAA is leu-
cine, due to its broad effects, including: important roles in
protein metabolism [2,3], glucose homeostasis [4], insu-
lin action [5], and recovery from exercise [6]. For 35 years
now, it has been known that leucine has anti-catabolic
properties [7]. The mechanism by which this occurs has
not been clearly established; however, it has been hypoth-
esized that the metabolite of leucine, a-ketoisocaproate
(KIC) may contribute to these results. To elaborate, when
Published: 3 January 2008
Nutrition & Metabolism 2008, 5:1 doi:10.1186/1743-7075-5-1
Received: 27 June 2007
Accepted: 3 January 2008
This article is available from: http://www.nutritionandmetabolism.com/content/5/1/1
© 2008 Wilson et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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ingested, leucine is transaminated into KIC [8], which
appears to decrease muscle breakdown [9-11]. However,
there are conflicting studies that suggest that these effects
may only take place under states of severe stress such as
starvation [12] or in severe burn victims [13]. It also
appears that the amount of BCAA supplementation affects
its benefits. Supplementing with 16 grams of BCAAs
resulted in several specific ergogenic benefits [14], while
supplementing with 3 grams in a similar study did not
[15]. Leucine is only partly converted into specific metab-
olites such as KIC, suggesting that this dose dependent
response is in part dependent on a high enough provision
of substrate to produce the metabolites necessary to opti-
mize leucine's ergogenic effects. Further evidence has indi-
cated that leucine's effects on protein degradation are
prevented when transamination is inhibited [16].
After leucine is metabolized to KIC, KIC is either metabo-
lized into isovaleryl-CoA by the enzyme a-ketoacid dehy-
drogenase in the mitochondria, or into beta-hydroxy-
beta-methylbutyrate (HMB) in the cytosol, by the enzyme
a-ketoisocaproate dioxygenase [8]. The majority of KIC is
converted into isovaleryl-CoA, while under normal condi-
tions; approximately 5% of leucine is metabolized into
HMB [8]. In perspective an individual would need to con-
sume 60 g of leucine in order to obtain 3 g of HMB, which
is the most frequently administered dosage for HMB in
studies.
A number of studies have indicated that HMB supplemen-
tation may elicit several ergogenic benefits, including anti-
catabolic [17], anabolic [18], and lipolytic effects [19],
among others [20]. Thus, it has been suggested that HMB
may partly be responsible for the benefits of leucine sup-
plementation. Given that HMB is a metabolite of leucine,
and can be consumed through both plant and animal
foods such as grapefruit and catfish, it has been credited as
a dietary supplement [21-23]. Supplemental HMB is com-
mercially available as calcium HMB monohydrate under
5 U.S. patents: 5,348,979 (a method for improving nitro-
gen retention), 5,360,631 (a method decreasing low-den-
sity and total cholesterol), 6,103,764 (a method for
increasing aerobic capacity of muscle), 4,992,470
(method of enhancing immune response), and 6,291,525
(method for improving a human's perception of his emo-
tional state), and 6,031,000 (composition comprising β-
hydroxy-β-methylbutyric acid and at least one amino acid
and methods of use).
HMB has been extensively used as an ergogenic aid; par-
ticularly among bodybuilders and strength/power ath-
letes, who use it to promote exercise performance and
skeletal muscle hypertrophy [24]. While numerous stud-
ies have supported the efficacy of HMB in exercise and
clinical conditions [25-27], there have been a number of
conflicting results. Therefore, the first purpose of this
paper will be to provide an in depth and objective analysis
of HMB literature. Special care is taken to present critical
details of each study in an attempt to explain possible rea-
sons for conflicting results seen. The second purpose of
this paper is to provide an in depth analysis of possible
mechanisms that HMB may exert its effects. Areas which
will be considered include HMB's capacity to prevent
muscle damage, lower protein degradation, and directly
stimulate protein synthesis.
Dependent measures used to study HMB supplementation
Several dependent measures have been utilized to study
the effects of HMB supplementation. These include per-
formance measures relating to dynamic [28], isometric
and isokinetic strength [19], as well as functionality exer-
cises in the elderly [29]. Other measurements include
questionnaires to measure the extent of delayed-onset
muscular soreness (DOMS) [30]; and various markers of
health including blood pressure, cholesterol, and
immune cell function [31]. Finally, given that HMB is gen-
erally considered to be an anticatabolic agent, markers of
muscle damage are also commonly analyzed [32]. During
physical exercise, muscle fiber disruption and subsequent
increased permeability allow leakage of creatine kinase
(CK), lactate dehydrogenase (LDH), and 3-methylhisti-
dine (3-MH) into plasma, which is inferred to reflect the
extent of incurred muscle damage [17,33,34]. Recently,
HMB's possible effects on protein synthesis as assessed
through uptake of radiolabeled phenylalanine has also
been examined [35].
Studies supporting the efficacy of HMB supplementation
The following sections will analyze various studies which
support the efficacy of HMB supplementation. Independ-
ent variables analyzed will include training experience,
age, and various catabolic states.
The efficacy of HMB supplementation for untrained
participants
Nissen et al. [36] examined the effects of HMB on muscle
metabolism and performance during resistance-exercise
in two experiments in healthy untrained males. Partici-
pants in the first experiment ingested 0, 1.5, or 3 g of HMB
daily, while weight lifting 3 days per week for 3 weeks.
Two dosages of HMB (0 or 3 g) were used in experiment
two, with weight training occurring 2–3 hours daily for 7
weeks. Results from experiment 1 found that HMB
decreased plasma markers of muscle damage (CK) and
protein degradation (3-MH) in a dose dependent
response with a range of 20–60%. Total weight lifted also
increased in a dose dependent manner (8, 13, and 18.4%
for 0, 1.5, and 3 grams of HMB, respectively). Finally, lean
body mass (LBM) increased with each increment increase
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in HMB ingestion (0.4, 0.8, and 1.2 kg of LBM gain for 0,
1.5, and 3.0 grams of HMB, respectively).
In the second experiment, LBM was significantly increased
with the HMB supplemented participants compared to
the non-supplemented participants at weeks 2 and 4–6
with no further differences seen during the final week
(week 7). Diminished improvements in LBM during the
final week of training may be due to accommodation of
the participants to the training stimulus. Participants
ingesting HMB increased their 1 repetition maximum (1-
RM) bench press by an average of 15 pounds, compared
to a 5-pound increase in the non-supplemented group.
In two acute studies, Van Someren et al. [32,37] examined
the effects of 3 grams of HMB and 0.3 grams of KIC on
indices of muscle damage following a single bout of
eccentric exercise in untrained male participants. Meas-
urements were taken at 1, 24, and 72 hours post-exercise.
Both studies indicated that DOMS, plasma CK, decre-
ments in 1-RM bicep curling strength, and decreased
range of motion (ROM) were reduced by HMB.
Gallagher et al. [19] investigated the effects of 0, 3, or 6
grams HMB supplementation in 37 untrained men on
strength and LBM during 8 weeks of resistance training
with 10 different resistance exercises, performed 3 times
per week at 80% of the participant's 1-RM. While results
found no significant differences between conditions in 1-
RM or body fat mass after 8 weeks of training, the HMB
supplemented conditions lowered plasma CK, and
increased peak isometric torque, various isokinetic torque
values and LBM to a greater extent than placebo. No dif-
ferences were found between 3 or 6 gram conditions.
Jowko et al. [18] investigated whether creatine and HMB
act by similar or different mechanisms in 40 participants,
who resistance trained and consumed creatine, HMB, or
creatine and HMB for a total of 3 weeks. Results found
that HMB, creatine, and the combination group gained
.39, .92, and 1.54 kg of LBM, respectively, above the pla-
cebo. The total amount of weight lifted increased above
the placebo on all exercises combined was 37.5, 39.1, and
51.9 kg for HMB, creatine, and the combination group,
respectively. Both HMB-supplemented conditions
decreased CK, urine urea nitrogen, and plasma urea, while
creatine supplementation alone did not decrease these
markers. The apparent additive effects of these supple-
ments indicate that creatine and HMB operate through
separate mechanisms.
The efficacy of HMB supplementation for experienced
athletes
Several studies have found that HMB supplementation
enhances LBM and indices of performance during resist-
ance training, independent of training experience. Nissen
et al. [28] investigated HMB supplementation on strength
and body composition in trained and untrained males
undergoing intense resistance training. Greater decreases
in body fat and increases in LBM were found with HMB
supplementation regardless of training status. Further,
there was an overall 55% greater increase in bench press
performance. Similarly, Panton et al. [38] examined the
effects of HMB during resistance training in 36 women
and 39 men, 20 to 40 years of age, with varying levels of
training experience for 4 weeks. The HMB group
decreased body fat to a greater extent (-1.1% vs. -.5%), and
had greater increases in upper body strength (7.5 vs. 5.2
kg), and LBM (1.4 vs. .9 kg) than the placebo group, inde-
pendent of training experience. Likewise, Thomson [39]
found an increase in leg extension 1-RM relative to pla-
cebo (14.7% vs. 4.8%) after 9 weeks of strength training in
34 resistance trained men, while Neighbors et al. [40]
reported that HMB decreased body fat and increased LBM
in experienced football players.
Finally, Nissen and Sharp [41] performed a meta-analysis
concerning dietary supplements postulated to augment
lean mass and strength gains during resistance training.
Studies between the years 1967 and 2001 were included,
if they met their strict experimental criteria, including at
least 3 weeks of resistance training, 2 or more times per
week. Over 250 supplements were analyzed; however,
only 6 met their criterion. Results found that only creatine
(18 studies) and HMB (9 studies including both trained
and untrained participants) had sufficient data support-
ing their ability to enhance LBM and various indexes of
performance. They found that HMB supplementation at 3
grams per day resulted in a net increase of .28% and 1.4%
per week for LBM and strength gains, respectively.
The efficacy of HMB has also been replicated in measures
of performance in experienced endurance athletes. Vuko-
vich and Geri [42] investigated the effects of HMB supple-
mentation on peak oxygen consumption (VO
2
peak) and
the onset of blood lactate accumulation (OBLA) in eight
endurance-trained master-level competitive cyclists, with
an average training volume of 300 miles per week. Partic-
ipants performed a graded cycle ergometer test until
exhaustion. All participants performed 3, 2-week supple-
mentation protocols consisting of either 3 grams of HMB,
leucine, or a placebo daily, while continuing their normal
training volume. Results from the graded exercise test
indicated that HMB increased the time to reach VO
2
peak
(8%), while leucine and the placebo did not. The VO
2
at 2
mM of lactate (OBLA) increased with HMB (9.1%) and
leucine (2.1%), but not with the placebo. Likewise, Vuko-
vich and Adams [43] found that 2 weeks of HMB supple-
mentation in experienced cyclists increased both VO2
peak and the time to reach VO
2
peak, while supplementa-
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tion with leucine or a placebo did not change these meas-
urements.
Knitter et al. [17] examined the effects of 3 grams of HMB
or a placebo on muscle damage during a 20 km run in 16
experienced male and female long distance runners.
Results showed a decrease in LDH and CK levels with the
HMB supplemented participants compared to the non-
supplemented participants. These results agreed with Byrd
et al. [44] who found that HMB or HMB combined with
creatine equally decreased the rise in muscle soreness fol-
lowing a 30 minute downhill run in 28 young, active
males; while the creatine only and placebo group did not.
The efficacy of HMB supplementation in the elderly
Several studies have examined if the ergogenic benefits of
HMB supplementation can be generalized to the elderly.
Vukovich et al. [29] showed that HMB supplementation
in 31 untrained, elderly men and women during an 8
week resistance training program resulted in increased
body fat lost (-.66 vs. -.03 %), and greater upper (13% vs.
11%) and lower body strength (13 % vs. 7 %) in the HMB
condition than the placebo.
Flakoll et al. [45] performed an experiment to determine
whether arginine and lysine, which may increase protein
synthesis, and HMB, which may decrease protein break-
down, could blunt sarcopenia. Fifty elderly women (M =
76.7 y) consumed a placebo or 2 grams of HMB, 5 grams
of arginine, and 1.5 grams of lysine daily. After 12 weeks,
there was a 17% increase in the "get-up-and-go" test in the
experimental group but no change in the placebo group.
There were also increases in limb circumference, leg
strength, handgrip strength, and a 20% increase in protein
synthesis over a 24-hour free-living period relative to the
placebo. Positive trends in fat-free mass gains (p = 0.08)
were also detected.
Vukovich et al. [46] investigated the efficacy of 3 grams of
HMB supplementation daily, for 8 weeks, in a group of
70-year old individuals, exercising 2 days per week.
Results indicated greater fat loss (-4.07 vs. .31 %) and
greater strength gains (17.2 vs. 8.3 %) during the first 4
weeks of supplementation in the HMB supplemented
condition versus the placebo. Panton et al. [47] investi-
gated the effects of HMB on muscle strength and func-
tional ability in 35 70-y old male and female individuals,
who participated in a 12-week resistance-training pro-
gram. Prior to and post training, changes in leg extension
and chest press capacity; time to get out of a chair, walk
6.6 meters, turn around, walk back to the chair, and sit
down (GUG); and time to walk 15.2 m at their regular
stride length were measured. No significant differences
were found between leg extension and chest press
strength, or walking time between the HMB and placebo
groups. However, GUG significantly (p < .05) improved
over the placebo with HMB supplementation.
The efficacy of HMB supplementation during states of
severe muscle catabolism
As a purported anti-catabolic agent, HMB supplementa-
tion has been examined under various muscle wasting sit-
uations. Soares et al. [48] showed that HMB
supplementation during hind limb immobilization of
adult mice resulted in less fiber damage, and greater mus-
cle fiber diameter (+6.9%). Consistent with these results,
studies have found that HMB supplementation decreases
performance decrements associated with bed rest [49,50].
Cohen [51] investigated the effects of HMB supplementa-
tion on changes in body composition during positive and
negative energy balances. Results found that HMB supple-
mentation maintained LBM to a greater extent than pla-
cebo while in a negative energy balance. This is consistent
with similar studies on the effects of amino acids and their
metabolites during negative energy balance [52-54].
Studies also indicate that HMB can reduce muscle loss
associated with diseases such as auto immunodeficiency
syndrome (AIDS) [55,56], and cachectic cancerous condi-
tions [35]. Collectively, these results led Alon et al. [57] in
a review on HMB to suggest that "continuing research in
HMB treatment of patients with advanced-stage disease
may potentially uncover methods to increase strength and
immunity and thus improve chances of survival (p.g.
14)."
Additional studies which support the efficacy of HMB
supplementation
The following section will analyze remaining studies
found which support the efficacy of HMB supplementa-
tion, but did not fit into the aforementioned categories.
Coelho and Carvalho [52] sought to determine if HMB
would be beneficial to 12 males between the ages of 50
and 72, with hypercholesterolemia, who exercised five
times per week for 4 weeks with a combination of endur-
ance and resistance training. Results showed that low den-
sity lipoprotein cholesterol (LDL-C) levels lowered from
172 to 123 mg/dl, LBM increased 6%, and performance
improved in every lift including leg presses (+1.8 kg), rear
lat pull-downs (+1.5 kg), and biceps curls (1.5 kg) in the
HMB group. The placebo group showed no differences in
cholesterol levels, but did improve performance in the leg
press (+1.3 kg) and rear lat pull-downs (+ 1.8 kg).
There is also evidence to suggest that HMB increases fat
oxidation in muscle cells [58,59]. Lastly, several animal
studies have found benefits from HMB including
decreased body fat [58], blood cholesterol [60], and mus-
cle proteolysis [61,62]. HMB supplementation in the
absence of exercise, however, does not appear to have
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ergogenic benefits in healthy individuals [63], suggesting
that HMB supplementation may only be effective with
increases in muscle catabolism.
Studies which do not support the Efficacy of HMB
supplementation
A number of studies conflict with research that supports
the efficacy of HMB supplementation. The following sec-
tion will analyze these studies.
Kreider et al. [64] used 40 experienced (M = 5 y) resistance
trained athletes who averaged 7 hours of training per week
for 28 days, while supplementing with 0, 3, or 6 g of HMB
daily. Participants were not monitored, but instead, were
instructed to maintain their normal training programs
during the experiment and record their training volume
before and after the experiment in a log. Consistent with
this, no differences were found in training volume per-
formed before and after supplementation with HMB;
while training intensity was not reported. Results showed
no significant decrease in markers of muscle damage, fat
mass, increased LBM or 1 RM performance in any of the
lifts measured in the placebo or HMB supplemented con-
ditions.
Slater et al. [65] had experienced resistance trained males
(M = 2 y) consume 3 g of HMB or a placebo for 6 weeks
while performing 2–3 sessions weekly of compound
movements (e.g. leg press, chins, bench press), for a total
of 24–32 sets, at a training intensity of 4–6 repetitions.
The training intervention significantly increased lean
body mass and total strength gains, but did not increase
any of the individual lifts. HMB supplementation had no
significant effect on LBM or strength or biochemical mark-
ers of muscle damage.
Paddon-Jones et al. [66] examined the effects of HMB on
symptoms of muscle damage following a bout of eccentric
exercise. Participants were non-resistance trained males,
who consumed HMB or a placebo, 6 days prior to and
after a bout of 24 maximal isokinetic eccentric contrac-
tions of the elbow flexors. Muscle soreness was measured
using a 10 point visual analogue scale, with a response
range from no soreness to extreme soreness. Arm girth was
measured with a metal tape measure, and muscle torque
was also measured at 15 minutes and 1, 2, 3, 7, and 10
days post exercise. The exercise bout significantly (p < .05)
increased muscle soreness, peaking at a score of 7; but
there was no significant difference between conditions in
muscle soreness, ROM, or elbow flexor strength. In a sim-
ilar experiment, Jennifer et al. [67] found no significant
difference in ROM or DOMS from HMB supplementa-
tion.
O'Connor and Crowe [20] investigated the effects of HMB
or HMB and creatine supplementation in elite, male
rugby players. Testing involved a multistage fitness test to
determine aerobic power and a 60 second maximal cycle
test to determine anaerobic capacity. No significant differ-
ences were showed in either condition for any of the
measures taken.
Jack et al. [68] examined the effects of daily HMB supple-
mentation on muscular strength (bench press, squats, and
power cleans) and body composition (body weight and
body fat) among elite collegiate football players who
trained 20 hours per week for 4 weeks. Results found no
significant benefits from HMB in bench press, squats, or
power clean performance, and no significant changes in
body composition. The lack of improvement overall from
this program lead the authors to conclude that, "...subjects
may have been over trained. The volume of exercise in this
study was higher than most other HMB-supplementation
studies. Although HMB may be most effective when
increasing training volume or intensity, the extremely
high total training load may have attenuated the potential
effectiveness of HMB to reduce muscle damage or protein
breakdown."
Similar to the aforementioned experiment, Hoffman et al.
[69] investigated the effects of HMB on power perform-
ance (using the Wingate anaerobic power test), indices of
muscle damage, and stress in 26 collegiate football play-
ers, during a 10-day training camp. Results found no sig-
nificant differences among conditions in markers of stress
(testosterone/cortisol ratio) and markers of muscle dam-
age (myoglobin and CK); finally, there was no significant
increase in performance in either condition pre to post
test.
Kreider et al. [70] examined the effects of 3 grams of HMB
on Division 1-A College Football players over 4 weeks of
training. Training was supervised, and consisted of 5
hours per week of resistance training with movements
such as bench press, shoulder press, and squats. Lifts were
prescribed at 1–3 sets, 2–8 reps, at 60–90% intensities.
Football sprints and agility drills were also performed 3
hours per week. Training significantly (p < .05) increased
total body mass, LBM, biochemical markers of muscle
damage, and decreased body fat percentage; however,
there were no significant differences between conditions
in any of these variables. Lastly, there was no significant
difference between conditions in combined lifting vol-
ume, or repetitive sprint performance.
Possible explanations for conflicting results
It is critical to analyze possible explanations for conflict-
ing results. To begin, in practically any investigation, the
possibility of obtaining contradictory results is high,
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based on the inherent noise (variability) found across
human participants [71]. The effects of variability in
humans on behavioral measures was first quantitatively
analyzed by Clark Hull in the 1940s [72]. Hull suggested
that performance was determined by seven components
such as internal drive states (e.g., motivation) that were
variable in nature. Since Hull, numerous studies have con-
firmed that results in human performance are not only
affected by physiological states, which are the primary tar-
get of HMB, but also through numerous other variables
including: the participant's social milieu (e.g., social facil-
itation/debilitation) [73], motivations (intrinsic and
extrinsic) [74], self-confidence [73], and current emotive
states [75]. According to Schmidt and Lee [71], the most
effective way to 'tease' out variable behavior is through
obtaining adequate sample sizes. Unfortunately, it is
often difficult for scientists to obtain large samples [76], as
indicated in a number of studies conducted on HMB in
which sample sizes are comprised of 8 or fewer partici-
pants [32,42,43,67], while the results obtained are gener-
alized to millions of people worldwide. Scientists are also
often limited to biased sampling, such as sampling by
availability [77,78] and convenience [76]. Thus, contra-
dictory studies should not be surprising in biological
research–rather, they should be expected.
A number of qualitative and quantitative solutions exist to
deal with this problem. Qualitatively, comprehensive
reviews are able to synthesize numerous studies in order
to find trends in the literature. Quantitatively the effect
sizes from hundreds of subjects across several studies can
be combined.
Other problems that occur lie in the validity of the testing
conditions. As will be discussed, certain tests may not
serve as a valid means of measuring what HMB supple-
mentation is purported to effect. A second problem that
stems from invalid measurements is that the conclusions
drawn from them may also be invalid. The following sec-
tion details specific examples of methodological prob-
lems, which may partly explain contradictory results
found in HMB-related literature.
The efficacy of HMB in trained athletes
While several studies have found benefits from HMB in
trained athletes [38-44], a number of studies have not
[64,68,69], leading some authors to conclude that HMB
supplementation may not be effective in trained individ-
uals [64,69]. Bloomer and Goldfarb [79] in a review on
sports supplements concluded that, "although it may be
somewhat reasonable to consider this nutrient [HMB]
during the initial stages of training, regular trainees may
not benefit much from its use." Similarly, Hoffman et al.
[69] posited that "if HMB supplementation has any ergo-
genic benefit in attenuating muscle damage, it is likely to
be most effective in the untrained population where the
potential for muscle damage to occur during exercise is
greatest."
Three possible explanations for the discrepancies found in
studies researching trained individuals will be discussed.
One was described by Hoffman et al. [69] and suggests
that the benefits of supplementing with HMB may be
maximized when muscular damage is heightened. For
example, Nissen et al. [63] investigated the effect of sup-
plementing with HMB on body composition and per-
formance in both exercising and non-exercising women.
Results showed HMB supplementation increased LBM, fat
loss, and performance in women who did exercise, but
not for women who did not exercise. In trained individu-
als, however, a stimulus must be substantially greater than
untrained individuals to cause significant disruption [80].
Of particular interest to HMB research is the finding that
the amount of muscular damage elicited by the same
eccentric bout of exercise decreases by the second bout
[81] (This concept will be discussed in further detail under
the section on mechanisms of HMB action). These find-
ings highlight the need for variability in training pro-
grams; particularly, in elite athletes. This concept can be
applied to the Kreider et al. [64] study. In this study, the
athletes were not monitored, but rather, instructed to
maintain their same training volume which they had pre-
viously performed prior to supplementation with HMB.
Since no significant decreases in markers of muscle dam-
age, fat mass, increased LBM or 1 RM performance in lifts
measured were found in any of the examined conditions,
this would suggest that athletes were accommodated to
the training stimulus. To properly examine the efficacy of
HMB, future studies are encouraged to design a perio-
dized, and monitored, strength program, which the ath-
letes are not accommodated to, that increases
performance across conditions.
A second explanation for conflicting results seen in expe-
rienced athletes consists of methodologies which contain
a lack of specificity between training and testing condi-
tions. As a brief review, over a century of evidence has
indicated that motor tasks are highly specific in nature
and have little transfer to other tasks (for excellent
reviews, see references [71,82-84]). One of numerous
examples of the extent of the specificity principle was
identified by Rivenes and Sawyer [85] who calculated the
amount of shared variance (r2) from over 1740 intercor-
relations between 60 motor tasks commonly used to
examine strength, flexibility, and power in 204 males of
the US Navy Academy. These investigators found an aver-
age of only 7 % commonality between tasks, indicating
that strength, flexibility, and power are task-specific.
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An understanding of the specificity principle can be
applied to a study by O'Connor and Crowe [20]. As previ-
ously discussed, the rugby players examined consumed
HMB during the course of their normal season, while test-
ing involved a multistage fitness examination to deter-
mine aerobic power and a 60 second maximal cycle test to
determine anaerobic capacity. No significant increases in
the tests were shown in the HMB or placebo conditions.
The lack of positive results may be explained by non-spe-
cific testing criteria relative to Rugby practice. For exam-
ple, cycling is not an intrinsic part of Rugby playing
conditions, while multistage fitness testing has been dem-
onstrated to have low shared variance with other tasks
[85-87].
Similarly, one measurement Hoffman et al. [69] used to
asses the efficacy of HMB in football players, was perform-
ance in the Wingate anaerobic power test. As would be
predicted by the specificity principle, results found no sig-
nificant increase in performance in either condition. A
third variable which may confound results concerns the
time periods used in studies to analyze advanced athletes.
For example, Hoffman et al. [69] analyzed HMB during a
short 10-day training camp. Slater and Jenkins [88] sug-
gested that (p.g. 112):
"It may be that for highly trained individuals, 4 weeks
of HMB supplementation is an inadequate time frame
to allow adaptations unique to HMB supplementation
to be identified. Studies involving longer periods of
supplementation, as used in some of the trials with
untrained volunteers, are needed to address this
issue."
It is interesting to note that all but 2 acute studies dis-
cussed in this manuscript [66,67], were found to support
the efficacy of HMB supplementation in untrained partic-
ipants. Therefore, it would appear that the focus of HMB
research should be on trained populations.
Other possible adjustments to future methodologies
A further problem suggested by the current authors is the
dosage of HMB administered. Currently, it is advised to
have 3 grams of HMB per day, spread into 3 equal dos-
ages. But few studies have actually investigated the opti-
mal dosage and optimal frequency of this supplement.
Optimal dosages will be discussed further on in this man-
uscript. An additional problem is that while there are
numerous dependent measures used to determine the
efficacy of HMB, few studies have actually fully utilized
these measurements.
In summary, while various studies in this review support
the efficacy of HMB supplementation, several studies did
not. These conflicting results may be partly attributed to
variability in humans, inadequate sample sizes, and
methodological issues including the specificity of testing
conditions, cases of overtraining, elicitation of an inade-
quate training stimulus in experienced participants, lim-
ited dependent variables, and short duration experiments.
Collectively, these results warrant further research on
HMB supplementation while taking into account these
various issues.
Clustering as a proposed problem against the validity of
HMB experiments
An argument sometimes proposed against the efficacy of
HMB supplementation, is that the studies concerning this
supplement tend to be conducted by similar authors
(clustered). For example, Jacques et al. [89] noted that in
the Nissen and Sharp [41] meta-analysis "the nine studies
on HMB clustered around three unrelated groups of
researchers (p.g. 2,180)."
The premise of the argument by Jacques et al. [89] was
that unassociated studies might elicit different results than
associated studies. Furthermore, it was proposed that
associated studies might elicit similar results to each
other, due to similar methodological techniques. How-
ever, this was not supported in the meta-analysis by Nis-
sen and Sharp [41]. Their results indicated that the average
effect size for the associated studies was .16, while the
unassociated studies had a similar effect size of .14. More-
over, the results sharply varied among the associated stud-
ies, with the effect sizes ranging from .03–.43, leading
Nissen and Sharp [89] to argue that, "With all effect sizes
for the HMB studies being generally similar and the ranges
of the associated studies including the unassociated stud-
ies, it seems unlikely that any source of systematic bias
explains the difference. The small numerical differences
are more likely to result from varying procedures, dosages,
measurements, and subject variability (p.g. 2, 182)."
A further argument proposed against the validity of HMB
investigations, is that the studies which have been done by
authors who profit from HMB sales, are subject to bias,
due to a conflict of interests, and therefore, may not be
trustworthy [90]. However, this argument can be classi-
fied as an Ad Hominem Circumstantial argument, which
is an argument suggesting that because someone may ben-
efit by taking a certain stance, their evidence is therefore,
invalid. While a bias may be cause for concern, it is unsub-
stantiated to conclude that the evidence presented by the
party in question, is therefore, invalid, and untrustworthy.
Finally, under the assumption that this argument was cor-
rect, the attractiveness of science is that it is replicable and
consequently self correcting. Therefore, if bias in studies
conducted on HMB, led to erroneous results, others
should not be able to find similar results in their experi-
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ments. To further validate experiments conducted on
HMB, the current authors propose that an updated meta-
analysis is needed, as the meta-analysis by Nissen and
Sharp [41] was done on a small sample of studies (9) and
was performed over 6 years ago. The meta-analysis will
want to pay close attention to various moderator variables
including, exercise modality, training loads, training expe-
rience, age, and several dependent measures such as mark-
ers of muscle damage, strength, and DOMS. Furthermore,
an additional analysis of the range of authors and Univer-
sities, which performed these studies would be helpful, to
further negate the issue of clustering.
Safety and health benefits of HMB supplementation
Studies have found that people are consuming more than
the recommended 3 g per day dosage of HMB [91]. Thus,
it is imperative to analyze the safety of various dosages of
HMB. Currently, studies have found no potential adverse
side effects when supplementing with HMB in both
humans consuming 3–6 grams daily [63,92-94] and ani-
mals consuming variable dosages [11,30,95-98]. In fact,
no adverse effects have been seen in animals consuming
enormous amounts of HMB, with a range between 8 and
5000 mg·kg-1·day-1 for a period of 1–16 weeks
[60,63,99]. For a 200 pound man, that would be an
upwards of 450 g of HMB per day.
Nissen et al. [36] performed an extensive two-part experi-
ment to test the effects of HMB supplementation on mus-
cle metabolism during resistance-exercise training. Results
found no adverse side effects from HMB supplementa-
tion. Similarly, Matthew et al. [29] investigated whether 3
grams of HMB daily would benefit 70-y old adults. Results
from this study also indicated no adverse effects from
HMB supplementation. Thus, HMB appears to be safe
when taken over several months, with 3–6 gram dosages
in humans. Additionally, as will be shown below, HMB
may actually be beneficial to various indexes of health.
Nissen, Sharp, and Panton [31] analyzed safety data from
nine studies in which humans were fed 3 g of HMB per
day. The studies were from 3 to 8 weeks in duration, and
included both males and females, young and elderly, exer-
cising and non-exercising participants. Results found that
HMB did not negatively affect any indicator of tissue
health or function. Further, HMB significantly (p < .05)
improved one measurement of negative mood state. It
was also found that HMB supplementation resulted in a
net decrease in total cholesterol (5.8%), a decrease in
systolic blood pressure (4.4 mm Hg), and a decrease in
LDL-C (7.3%). However, HMB did not significantly lower
LDL-C in subjects with accepted normative levels of cho-
lesterol (< 200 mg/dl), suggesting that HMB is more effec-
tive at lowering LDL-C when cholesterol levels are high.
Consistent with this, Coelho and Carvalho [52] found
that HMB supplementation resulted in a significant (p <
.05) decrease in LDL-C levels, going from 172 to 123 mg/
dl, in individuals with hypercholesterolemia.
Gallagher et al. [93] investigated the effects of differing
amounts of HMB (0, 3, and 6 g) on hematology and
hepatic and renal function during 8 weeks of resistance
training in untrained men. Results found no adverse
effects from HMB supplementation on hepatic enzyme
function, lipid profile, renal function, or the immune sys-
tem. Evidence also suggests HMB may help the immune
system and increases wound repair [98].
In summary, available evidence suggests that HMB sup-
plementation is safe, and may potentially improve several
markers of health.
Optimal dosage of HMB supplementation
Most studies advise taking 3 grams of HMB daily for max-
imal benefit [[31,36,41,43], &[38]]. For instance, Nissen
et al. [36] found that HMB in servings of 0, 1.5, and 3
grams improved performance in a dose dependent man-
ner. However, it would have been interesting to observe
the efficacy of higher dosages. More recently, Gallagher et
al. [19] found that 6 grams of HMB did not improve LBM
or strength gains over 3 grams.
To the current authors knowledge, this study by Gallagher
et al. [19], along with the previously discussed Kreider et
al. [64] study in trained individuals are the only studies to
investigate the efficacy of dosages of HMB above 3 grams.
Thus, it would be advisable that other scientists replicate
these results under varying circumstances.
Latency of peak of HMB concentration following ingestion
Vukovich et al. [100] investigated the digestion patterns of
HMB, and the effect of glucose supplementation on HMB
in 2 studies. Eight males consumed 1 g of HMB in study 1
and 3 g of HMB, or 3 g of HMB with 75 g of glucose in
study 2. In the first study, plasma HMB peaked at 120
nmol/mL 2 hours after ingestion. Approximately 14%
(0.14 g) of the HMB accumulated in the urine following
ingestion of one g of HMB. In the second study, plasma
HMB peaked at 487 nmol/mL 1 hour after ingestion of 3
g of HMB and was significantly lower at 352 nmol/mL 2
hours after ingestion of 3 g HMB and glucose. The authors
suggested that the delay in peak concentrations of HMB
coupled with research indicating slowed gastric emptying
in response to increasing glucose concentrations, in solu-
tion suggests lowered plasma concentrations are at least
partly due to gastric emptying. Based on the finding that
glucose stimulated insulin secretion has been found to
enhance skeletal muscle uptake of amino acid based sub-
stances it is possible that this hormone may have effected
HMB concentrations through a similar mechanism. Cur-
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rently the latter contention is speculative as the metabolic
fate of HMB is unknown. Resolution of this uncertainty
led the authors to suggest a further analysis using the
hyperinsulinemic clamp technique. Approximately
29%(0.87 grams) of the ingested HMB accumulated in
the urine following ingestion of HMB and glucose or
HMB alone, with no significant differences between the
two. In summary, plasma HMB peaks faster at 3 (60 min-
utes) vs. 1 (120 minutes) gram doses, and is delayed when
consumed with glucose (60 vs. 120 minutes). Further,
about 71 to 86% of consumed HMB is retained by the
body, with a greater percentage of HMB being retained at
1 vs. 3 g dosages, independent of glucose consumption.
Lastly, HMB has a half-life of approximately 2.5 h, and
reaches baseline levels 9 hours after consumption.
Some authors have recommended that HMB should be
standardized according to body weight. Using this frame-
work, it is advised to have 38 mg/kg of body weight per
day (equivalent to 17.3 mg/lb of body weight per day)
[19].
In summary, when supplementing with HMB, current evi-
dence suggests that 1 gram of HMB should be consumed
3 times per day, for a total of 3 g of HMB daily (or 38 mg/
kg of LBM). However, clearly more studies are needed to
determine the optimal dosage and frequency of HMB sup-
plementation, and the overall efficacy of HMB supple-
mentation as an ergogenic aid.
Mechanisms of action proposed for HMB
HMB's mechanisms of action are generally considered to
operate through its capacity to stabilize the sarcolemma
[94] and/or attenuate proteolytic pathways [35,101]. The
role of HMB in stabilizing the sarcolemma is known as the
Cholesterol Synthesis Hypothesis (CSH), while its antag-
onistic effects on proteolytic pathways appear to operate
through the ubiquitin-proteasome dependent pathway
(Ub-pathway). The following three sections will discuss
(1) the CSH, (2) the effects of HMB on the Ub-pathway,
and finally (3) how these mechanisms may interact to
enhance both muscle tissue accretion and indexes of exer-
cise performance (Figure 1)
The Cholesterol Synthesis Hypothesis (CSH)
According to the CSH, a damaged muscle cell may lack the
capacity to produce adequate amounts of cholesterol
needed for various cellular functions, including the main-
tenance of sarcolemmal integrity [31]. This is particularly
important in muscle tissue, which relies heavily on de-
novo cholesterol synthesis [31]. Cholesterol is formed
from Acetyl-CoA, in which the rate limiting step, catalyzed
by the enzyme HMG CoA reductase, is the formation of
the cholesterol precursor mevalonic acid from HMG-CoA.
The majority of HMB is converted into HMG-CoA reduct-
ase [31,102]. Therefore, increased intramuscular HMB
concentrations may provide readily available substrate for
the synthesis of cholesterol needed to form and stabilize
the sarcolemma [31,36].
Support for this hypothesis has come from the finding
that the inhibition of cholesterol synthesis results in
impaired muscular function [103], heightened muscular
damage [104], and finally, muscle cell necrosis [105]. Par-
adoxically, studies have found that HMB is associated
with lowered total and LDL-C levels, but only in cases of
hypercholesterolemia (i.e., > 200 mg/dl) [31,52]. While
no complete explanation has been offered, these effects
may be related to the inclusion of calcium during HMB
supplementation (100–200 mg per g of HMB). Research
indicates that as low as a gram calcium supplementation
lowers serum cholesterol concentrations through increas-
ing bile acid excretion, leading to increased use of endog-
enous cholesterol from the liver for regenerative processes
[106].
HMB's role in the production of mevalonic acid, may also
serve other functions critical for muscle function [107].
Mevalonic acid, produced from HMG-CoA reductase is a
precursor of coenzyme Q and dolichols [108], which are
critical for myocyte proliferation [108]. Coenzyme Q also
plays a major role in mitochondrial electron transport
function [108,109].
Possible onteraction of HMB with the ubiquitin-
proteasome proteolysis dependent pathway
A number of new developments have occurred in the
analysis of proteolytic pathways that HMB may interact
with. The three major pathways through which proteoly-
sis occurs are lysosomal, calcium activated calpain (CAC),
and Ub-pathways [26,110]. Extra cellular proteins such as
insulin receptors appear to be degraded through the lyso-
somal pathway [110], while the CAC system may have a
role in the initial degradation of intracellular proteins
[111]. Finally, the Ub-pathway appears to be responsible
for specific intracellular protein degradation [26].
Increased activity of the Ub-pathway is common in condi-
tions which elicit increased muscular proteolysis
[112,113] including: antigravity conditions [114,115],
cancer [26,101], limb immobilization [75], starvation
[112], denervation [116], lowering of activity [117], and a
variety of exercise conditions [118,119]. The efficacy of
HMB has been demonstrated in both diseased [26,56]
and exercise induced states of catabolism [36], indicating
that it may operate through direct or indirect interference
of the Ub-pathway.
Research on the effects of HMB on the Ub-pathway has
been primarily conducted in the Tisdale lab, with notable
studies conducted by Smith et al. [26,101], and more
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recently Baxter and colleagues [35]. Smith et al. [101]
investigated the effects of HMB supplementation in
cachexic tumour bearing mice. The study found that HMB
increased muscle wet weight of the gastrocnemius, and
lowered protein degradation relative to control animals.
This was associated with a decrease in activity and expres-
sion of the Ub-pathway. Intriguingly enough, it was found
that HMB supplementation also increased protein synthe-
sis in the gastrocnemius.
To further isolate possible mechanisms involved in prote-
olytic pathway depression, Smith et al. [26] administered
HMB to murine myotubes exposed to Proteolysis-Induc-
ing Factor (PIF), which is associated with the up-regula-
tion of the Ub-pathway. The increases in proteolysis
through PIF administration were completely attenuated
by HMB. These findings were accompanied by a decrease
in the activity of protein kinase C and accumulation of
nuclear factor-kappa B, which are critical components in
PIF up-regulation of the Ub-pathway.
More recently Baxter et al. [35] investigated a possible
mechanism by which HMB might stimulate protein syn-
thesis. Because HMB is a metabolite of leucine, Baxter et
al. [35] examined if HMB was able to activate protein syn-
thesis through a similar mechanism as leucine. Leucine
appears to stimulate protein synthesis through activation
of mammalian target of rapamysin (mTOR) [120-122], a
protein kinase indicated to up-regulate protein synthesis
at the level of translation initiation [121].
Baxter et al. [35] utilized a similar protocol to the Smith et
al. [101] study. However, to examine if HMB was operat-
ing through an mTOR dependent mechanism, rapamycin,
a specific inhibitor of mTOR, was administered. HMB
supplementation attenuated muscle tissue loss, which
Possible Mechanisms of HMB actionFigure 1
Possible Mechanisms of HMB action. HMBs proposed mechanisms of action include (A) Increased sarcolemal integrity via
conversion to HMG-CoA reductase, (B) enhanced protein synthesis via the mTOR pathway and (C) depression of protein deg-
radation through inhibition of the Ubiquitin pathway.
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was partly attributed to an increase in protein synthesis
relative to the control mice. However, Rapamycin attenu-
ated the increase in protein synthesis, suggesting that
HMB is operating either directly or indirectly through an
mTOR-specific mechanism.
The role of HMB in attenuating the Ub-pathway in exer-
cise induced proteolysis remains to be directly investi-
gated. What studies do indicate, however, is that exercise
appears to be associated with a three phase Ub-pathway
response (for a review, see reference [117]). Phase one
begins immediately following initiation of exercise and
transiently (minutes to hours) increases the conjugation
of Ub to substrate proteins [117]. This phase reverses after
exercise has ended [99]. Phase 2, occurring 6–24 hours
following exercise involves an increased expression of the
Ub-pathway and is thought to be involved in remodeling
of damaged muscle tissue [117]. Finally phase three
occurs days to weeks after exercise and is associated with a
return of Ub-proteasome expression to baseline levels
[117]. Results indicate that amino acid supplements deliv-
ered prior to and after exercise markedly increases protein
balance, and that this increase is associated with greater
blood flow to the muscle tissue (for a review, see reference
[3]). Future research implications involve studying the
effects of the timing of HMB ingestion relative to exercise.
If HMB attenuates the Ub-pathway, then its administra-
tion prior to exercise may specifically decrease the phase 1
Ub-proteasome response, while post exercise feedings
may have specific effects for the phase 2 response.
Lastly, current research indicates that when a given train-
ing stimulus remains similar that the Ub-pathway
response lowers with each successive exercise session
[123]. If HMB is operating through the Ub-pathway to
decrease muscle damage during exercise, then this finding
reinforces the importance of incorporating variability dur-
ing training in HMB experiments; particularly in experi-
enced athletes who are more resistant to muscle damage.
Applications of HMB mechanisms to indices of
performance and lean mass
This section addresses how HMB's proposed mechanisms
of action interact with and explain improvements in
indexes of human performance and body composition.
Increased protein accretion is a function of the difference
between protein synthesis and protein degradation [25].
As indicated above, studies have shown that HMB may
affect both functions [35], thereby increasing the ratio of
protein synthesis to degradation [26], with a subsequent
positive change in LBM. Changes in strength are largely
due to neurological adaptations early in practice (changes
in motor unit recruitment, asynchronous to synchronous
contractions, etc.), while increases in lean muscle mass,
which increases the capacity off the body to produce force,
accounts for a greater percentage of strength gains later on
[84]. Currently, the ability of HMB to increase indices of
strength have been attributed to the changes observed in
lean mass. However, research has not examined possible
neurological adaptations facilitated by HMB supplemen-
tation.
HMB's effects on performance across time has been an
area of interest. One study [36] indicated HMB was effec-
tive early in a training intervention (< 6 weeks), with
lower benefits seen in the latter part of the intervention
(week 7). Evidence from Willoughy et al. [123] suggests
that Ub expression is lowered when participants are
exposed to repeated bouts of similar training stimuli. If
HMB is operating through the Ub-pathway then future
studies will want to correlate Ub-expression with HMBs
effectiveness. Ub may also serve as a dependent measure
for the effectiveness of a stimulus to elicit enough disrup-
tion in athletes for HMB to be effective.
As discussed, some studies have indicated that HMB may
increase body fat loss. For instance, Jack et al. [68] found
that HMB increased beta-oxidation of the fatty acid palmi-
tate by 30%. If HMB does lower body fat, these findings
may be related to HMB's role in preventing the break-
down or stimulating the synthesis of proteins associated
with the oxidative system. For instance, decreases in the
breakdown of mitochondria, or increases in its synthesis,
would potentially elevate an individual's capacity to
metabolize fat. Evidence suggests that the success of fat
loss interventions, which include exercise are associated
with increased mitochondrial content and size [124].
HMB may also influence mitochondrial function through
an increase in Coenzyme Q. However, to date no direct
studies have investigated this proposal. Finally, increased
muscle mass from HMB supplementation could increase
participants metabolic rate, effectively increasing fat oxi-
dation.
HMB's possible effects on sparing or enhancing the func-
tion of oxidative organelles, has received support from
studies indicating that it can improve performance in
exercise highly reliant on the oxidative system [42]. Dur-
ing HMB supplementation participants demonstrate a
higher OBLA and VO
2
peak [42]. The primary mechanism
to clear lactic acid is through oxidation [42]; therefore,
these results may be explained through increased mito-
chondrial content, size, or functional changes. Higher
VO
2
peaks may also be attributed to increased muscle tis-
sue accretion [42].
Studies have indicated that HMB may lower blood pres-
sure [31]. These effects may partly be attributed to the
inclusion of calcium, [125] as the degree to which HMB
lowers blood pressure is not much greater than what cal-
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cium normally does by itself [31]. Lastly, HMB appears to
increase immune function in animals [126]. For example,
HMB exposure increases macrophage proliferation and
functionality as indicated through phagocytosis. HMB
may exert its effects through an mTOR related mecha-
nism, as this kinase is critical for lymphocyte proliferation
[127].
Implications for future research
The first purpose of this paper was to provide an in depth
and objective analysis of HMB research. A reflection on
the data discussed in this analysis leads to several future
research implications. Currently, there is much conflicting
evidence in the HMB literature, with some studies show-
ing an ergogenic effect, and others not. In this manuscript,
we have written a qualitative analysis on why this may be
the case; we believe the next logical step should be a quan-
titative review. The last meta-analysis to be conducted on
HMB was over 6 years ago by Nissen and Sharp [41], and
only 6 studies were examined. We suggest that a future
meta-analysis pay close attention to various moderator
variables including, exercise modality, training loads,
training experience, age, and several dependent measures
such as markers of muscle damage, strength, and DOMS.
An additional analysis of the range of authors and Univer-
sities, which performed these studies would be helpful, to
further address the issue of clustering and bias.
Current evidence suggests that increasing HMB dosages
up to 3 grams will improve strength and lean body mass,
and lower muscle damage in a dose dependent manner
[36]. To date, only two studies [19,64] have investigated
the efficacy of higher dosages of HMB (3 vs. 6 grams per
day), with no additional benefits found with higher dos-
ages, suggesting that 3 grams (or 38 mg/kg of body weight
per day) is an optimal dosage for HMB. However, we pro-
pose that this optimal dosage may change with varying
degrees of muscle damage and catabolic stimuli. As a pur-
ported agent capable of strengthening sarcolemal intregity
and blunting proteolysis, HMB appears to exert its maxi-
mum effects during damaging and catabolic states
induced by factors such as exercise [36], negative energy
balance [51], and cancer [35]. Currently, no study has
investigated the optimal dosage of HMB under varying
degrees of catabolism. Two possible ways to test this
would be to 1.) combine two catabolic stimuli (i.e. aging
and a negative energy balance) and 2.) include varying
degrees of damaging stimuli (i.e. 5 sets of squats vs. 10
sets). A lack of muscle sarcolemal disruption may partially
explain conflicting results in advanced athletes, who are
more resistant to muscle damage [123]. Therefore, future
studies on advanced athletes are encouraged to incorpo-
rate a closely monitored, and relatively novel periodized
strength program, designed to increase performance
across conditions, and to cause significant muscle tissue
damage. Further, chronic studies are rare in the literature,
with few studies lasting longer than 4–8 weeks in duration
[88]. Therefore, extended experiments are in need.
Two additional factors in optimal HMB administration
concern nutrient timing and the effects of acute HMB
administration. Recent evidence has suggested that vari-
ous indexes of anabolism (e.g. protein synthesis) are
greater when amino acids are consumed post exercise rel-
ative to rest [128], and pre-exercise relative to post exercise
[129]. These results have been commonly attributed to
enhanced blood flow and nutrient delivery to the mus-
cles. Therefore, it would be of interest to see if these results
with amino acids can be extended to HMB supplementa-
tion. Secondly HMB is generally administered greater than
or equal to 2 weeks prior to examining its effects on indi-
cators of muscle damage. We recently investigated the
acute timing effects of HMB on maximal voluntary con-
traction (MVC) and visual analogue scale (VAS) deter-
mined soreness in 16 non-resistance trained men (18–28
yr) randomly assigned to HMB-PRE or HMB-POST
groups. All subjects performed an eccentric damaging pro-
tocol (55 maximal eccentric unilateral knee extension/
flexion contractions) on two separate occasions, per-
formed on the dominant or non-dominant leg in a coun-
ter-balanced crossover design. HMB-PRE (N = 8) received
3 grams of HMB before and a placebo after exercise, or a
placebo before and after exercise. HMB-POST (N = 8)
received a placebo before and 3 grams of HMB after exer-
cise, or a placebo before and after exercise. Tests for MVC
and soreness were recorded prior to all the way up to 72
hours post exercise. While there was an overall reduction
in MVC and increase in soreness in the quadriceps and
hamstring following exercise, we found no acute or timing
differences, suggesting acute HMB consumption may not
influence muscle soreness and strength whether adminis-
tered prior to or following exercise. It is important to note
that unlike past studies we administered HMB only prior
to or following exercise, with no loading period. However
the acute timing effects on indirect markers of sarcolemal
integrity remain to be analyzed, but are currently under
investigation in our lab. Pathways which may be affected
by the timing of acute HMB supplementation including
mTOR and Ub-proteolytic pathways will also need to be
investigated. Finally studies examining the timing of HMB
over a chronic periods (e.g > 12 weeks) need further
research.
The second purpose of this paper was to provide a com-
prehensive discussion on possible mechanisms, which
HMB may operate through. Currently, the most readily
discussed mechanism has been attributed to HMB as a
precursor to the rate limiting enzyme to cholesterol syn-
thesis HMG-coenzyme A reductase. This hypothesis sug-
gests that HMB may provide readily available substrate for
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the synthesis of cholesterol needed to form and stabilize
the sarcolemma [31,36]. Paradoxically, studies have
found that HMB is associated with lowered total and LDL-
C levels, but only in cases of hypercholesterolemia (i.e., >
200 mg/dl) [31,52]. While no complete explanation has
been offered, these effects may be related to the inclusion
of calcium during HMB supplementation (100–200 mg
per g of HMB). Research indicates that as low as a gram
calcium supplementation lowers serum cholesterol con-
centrations through increasing bile acid excretion, leading
to increased use of endogenous cholesterol from the liver
for regenerative processes [106]. Future studies should
examine the effects of HMB on cholesterol, while control-
ling for calcium intake.
An increase in research has been directed towards possible
proteolytic pathways HMB may operate through. Evi-
dence from cachectic cancer studies suggests that HMB
may inhibit the ubiquitin-proteasome proteolytic path-
way responsible for the specific degradation of intracellu-
lar proteins. HMB may also directly stimulate protein
synthesis, through an mTOR dependent mechanism. It
would be of interest to see if the effects of HMB on the Ub/
pathway and mTOR can be extended to the exercise
domain. Future studies are therefore, encouraged to
broaden the scope of dependent measurements taken.
Conclusion
The first purpose of this paper was to provide an in depth
and objective analysis of HMB research. While various
studies analyzed in this manuscript support the efficacy of
HMB as an effective ergogenic aid for athletes that
decreases DOMS, markers of muscle damage, and body
fat, while increasing various markers of performance,
including LBM and strength in resistance trained athletes,
and OBLA and VO2 peak in endurance trained athletes, a
number of studies analyzed did not support the efficacy of
HMB supplementation. The current authors suggest that
these conflicting results may in part be attributed to the
variability in humans, inadequate sample sizes, and
methodological issues such as the specificity of testing
conditions, cases of overtraining, elicitation of an inade-
quate training stimulus in experienced participants, lim-
ited dependent variables, and short duration experiments.
Collectively, these results warrant further research on
HMB supplementation while taking into account these
various issues. Tables 1 and 2 summarize the results from
the HMB literature.
There is compelling evidence that HMB supplementation
may be useful for clinical muscle wasting conditions
including AIDS, cancer, bed-rest, and during periods of
caloric deficits. HMB also appears to be safe, and may
improve various markers of health, including blood pres-
sure and LDL-cholesterol. When supplementing with
HMB, current evidence suggests that 1 g of HMB should be
consumed 3 times per day, for a total of 3 g of HMB daily
(or 38 mg/kg of bodyweight). However, more studies are
needed to determine the optimal dosage and frequency of
HMB supplementation, and the overall efficacy of HMB
supplementation as an ergogenic aid for athletes.
The second purpose of this paper was to provide an in
depth analysis of possible mechanisms that HMB may
exert its effects. Results from this review showed that HMB
appears to primarily exert its effects through protective
and anticatabolic mechanism. The prevailing explanation
is the cholesterol synthesis hypothesis. However, recent
studies have shown that HMB's anticatabolic effects are at
least in part mediated by attenuation of the activation and
increased gene expression of the ubiquitin-pathway. Fur-
thermore, there is evidence that HMB may directly
increase protein synthesis.
Competing interests
The author(s) declare that they have no competing inter-
ests.
Acknowledgements
The authors would like to thank Dr. Lynn Panton for her expert critique of
this paper. And Joel Baxter for his thoughtful insights and expertise into
mechanisms of HMB administration.
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Table 1: Studies Which Support the Efficacy of HMB supplementation in Varying Populations
Experiment Participants Dosage/Duration Biochemistry Performance Body composition
Nissen et al. [36] Untrained 0, 1.5, or 3 g/day for 7
weeks
CK & 3-MH decreased,
dose dependent
Greater Total weight lifted,
dose dependent
Greater LBM, dose
dependent
Van Someren et al.
[32, 37]
Untrained 3 grams of HMB and .3
grams of KIC, prior to a
single bout eccentric
exercise
CK down Greater 1-RM bicep curl and
ROM, lower DOMS
NR
Jowko et al. [18] 40 M, untrained P, 3 gram HMB, HMB
&creatine, or creatine
Only HMB lowered CK,
urine urea nitrogen, and
plasma urea
HMB & creatine additive
effect on weight lifted
HMB & creatine
additive effect on LBM
Gallagher et al.
[19, 93]
37 M, untrained P, 38 or 76 mg/kg for 8
weeks
CK, no effect on lipid
profile, immune system,
or renal function
Greater Isokinetic &
Isometric torque,
independent of dose.
Greater LBM, no effect
on FML, independent of
dose
Nissen et al. [28] 40 M, trained and
untrained
P or 3 g/day for 4
weeks
NR Greater bench press 1-RM Increase in LBM and
FML
Panton et al. [38] 36 F, 39 M, varying
training experiences
P or 3 g/d for 4 weeks NR Greater upper body strength Greater LBM & FML.
Thomson [39] 34 experienced weight
lifters
P or 3 g/d for 9 weeks NR Greater leg extension
strength
NR
Neighbors et al. [40] Experienced collegiate
football players
P or 3 g/d NR NR Greater LBM and FML
Nissen & Sharp [41] Meta-analysis, 9 studies P or 3 g/day NR .28% greater weekly
strength
1.4% greater weekly
LBM
Nissen et al. [63] 37 F P or 3 g/day for 4
weeks
No effect Greater Bench Press 1-RM Greater LBM
Vukovich and Geri
[42], Vukovich and
Adams [43]
8 experienced cyclists 3 g/day HMB, leucine,
or P, 2 weeks for each
supplement.
NR HMB increased time to
reach VO2 peak, and VO2 at
OBLA.
NR
Knitter et al. [17] 16 F & M, experienced
long distance runners
P or 3 g/day prior to 20
KM run.
Lower LDH and CK. NR NR
Byrd et al. [44] 28 active M P or 3/g HMB or
creatine daily prior to
downhill run
NR HMB lowered soreness. NR
Vukovich et al. [29] 31 untrained M & F P or 3 g/day for 8
weeks
NR Greater upper and lower
body strength
Greater FML, no effect
on LBM.
Vukovich et al. [46] 31 elderly M & F P or 3 g/day for 8
weeks
NR Greater Leg strength Greater FML, trend for
LBM (P > .06)
Flakoll et al. [45] 50 elderly F P or 2 g of HMB, 5 g of
arginine, and 1.5 g of
lysine daily.
Greater protein synthesis Greater functional mobility,
leg and handgrip strength.
Trend FML (P=.08)
Panton et al. [47] 35 elderly M & F P or HMB for 8 weeks NR Greater Functional mobility No effect
Soares et al. [48] Adult mice HMB prior to hind limb
immobilization
NR NR Less fiber damage,
greater fiber diameter.
Cohen [51] Dieting humans, in
negative energy balance
3 g/day of HMB NR NR Greater maintenance
LBM
Coelho and Carvalho
[52]
12 elderly M 3 g/day of HMB for 4
weeks
Lower LDL-C Greater weight lifting
strength
Greater LBM
M = Male; F = Female; LBM = Lean body mass; P = Placebo; FML = Fat mass lost; CK = Creatine kinase; LDL-C = Low density lipoprotein cholesterol; NR = Not
reported; 3-MH = 3-methylhistidine.
Table 2: Studies Which do not Support the Efficacy of HMB Supplementation in Varying Populations
Experiment Participants Dosage/Duration Biochemistry Performance Body Composition
Kreider et al. [64] 40 experienced
resistance trained M
0, 3, or 6 g/day for 4 weeks No effect markers of
muscle damage
No effect on strength No effect on LBM
or FM
Slater et al. [65] Experienced resistance
trained M
0, 3 g/day for 6 weeks No effect markers of
muscle damage
No effect on strength No effect on LBM
or FM
Paddon-Jones et al. [66],
Jennifer et al. [67]
Untrained M 0, or 3 g/day, 6 days prior to a
single bout eccentric exercise
NR No effect on soreness, ROM,
or elbow flexor strength
NR
O'Connor and Crowe
[20]
Elite M rugby players P, 3 g/day HMB, or creatine
and HMB, during season.
NR No effect on multistage fitness
test or maximal cycle test
NR
Jack et al. [68] Elite collegiate football
players
0, 3 g/day for 4 weeks during
football training
NR No effect on weight lifting
strength
No effect on body
composition
Jay et al. [69] 26 elite collegiate
football players
0, 3 g/day for 4 weeks during
10 day training camp
No effect markers of
muscle damage
No effect on performance No effect on LBM
or FM
Kreider et al. [70] Division 1-A College
Football
0, 3 g/day during 4 weeks of
resistance training
No effect markers of
muscle damage
No effect on strength or sprint
performance
No effect on LBM
or FM
M = Male; F = Female; LBM = Lean body mass; P = Placebo; FM = Fat mass; NR = Not reported.
Nutrition & Metabolism 2008, 5:1 http://www.nutritionandmetabolism.com/content/5/1/1
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References
1. Harper AE, Miller RH, Block KP: Branched-chain amino acid
metabolism. Annu Rev Nutr 1984, 4:409-454.
2. Garlick PJ: The role of leucine in the regulation of protein
metabolism. J Nutr 2005, 135(6 Suppl):1553S-6S.
3. Wilson J, Wilson G: Contemporary issues in protein require-
ments and consumption for resistance trained athletes. Jour-
nal of the International Society of Sports Nutrition 2006, 3(1):7-27.
4. Layman DK: The role of leucine in weight loss diets and glu-
cose homeostasis. J Nutr 2003, 133(1):261S-267S.
5. Patti ME, Brambilla E, Luzi L, Landaker EJ, Kahn CR: Bidirectional
Modulation of Insulin Action by Amino Acids. J Clin Invest 1998,
1;101(7):1519-29.
6. Mero A: Leucine supplementation and intensive training.
Sports Med 1999, 27(6):347-58.
7. Hider RC, Fern EB, London DR: Relationship between intracel-
lular amino acids and protein synthesis in the extensor digi-
torum longus muscle of rats. Biochem J 1960, 114(2):171-178.
8. Van Kovering M, Nissen SL: Oxidation of leucine and alpha-
ketoisocaproate to b-hydroxy-b-methlbutyrate in vivo. Am J
Physiol Endocrinol Metab 1992, 262:27.
9. Chua BD, Siehl L, Morgan HE: Effect of leucine and metabolites
of branched chain amino acids on protein turnover in heart.
J Biol Chem 1979, 254:8358-8362.
10. Hong SOC, Layman DK: Effects of leucine on in vitro protein
synthesis and degradation in rat skeletal muscles. J Nutr 1984,
114:1204-1212.
11. Van Koevering MT, Gill DR, Smith RA, Owens FN, Nissen S, Ball RL:
Effect of β-hydroxy-β-methyl butyrate on the health and per-
formance of shipping-stressed calves. Oklahoma State Univ Res
Rep 1993:312-31.
12. Cersosimo E, Miller BM, Lacy WW, Abumrad NN:
Alpha-ketoiso-
caproate, not leucine, is responsible for nitrogen sparing
during progressive fasting in normal male volunteers. Surg
Forum 1983, 34:96-99.
13. Aussel C, Cynober L, Lioret N, Coudray-Lucas C, Vaubourdolle M,
Saizy R, Giboudeau J: Plasma branched-chain keto acids in burn
patients. Am J Clin Nutr 1986, 44(6):825-831.
14. Hefler SK, Wideman L, Gaesser GA, Weltman A: Branched-chain
amino acid (BCAA) supplementation improves endurance
performance in competitive cyclists. Med Sci Sports Exerc 1995,
27:S149.
15. Vukovich MD, Sharp RL, Kesl LD, Schaulis DL, King DS: Effects of an
amino acid supplement on adaptations to combined aerobic
and anaerobic cycling training. Int J Sport Nutr 1997, 7:298-309.
16. Mitch WE, Clark AS: Specificity of the effects of leucine and its
metabolites on protein degradation in skeletal muscle. Bio-
chem J 1984, 222:579-86.
17. Knitter AE, Panton L, Rathmacher JA, Petersen A, Sharp R: Effects
of β-hydroxy-β-methylbutyrate on muscle damage after a
prolonged run. J Appl Physiol 2000, 89:1340-1344.
18. Jowko E, Ostaszewski P, Jank M, Sacharuk J, Zieniewicz A, Wilczak J,
Nissen S: Creatine and β-hydroxy-β-methylbutyrate (HMB)
additively increase lean body mass and muscle strength dur-
ing a weight-training program. Nutr 2001, 17:558-566.
19. Gallagher PM, Carrithers JA, Godard MP, Schulze KE, Trappe S: β-
hydroxy-β-methylbutyrate ingestion, part I: Effects on
strength and fat free mass. Med Sci Sports Exerc 2000,
32:2109-2115.
20. O'Connor DM, Crowe MJ: Effects of beta-hydroxy-beta-meth-
ylbutyrate and creatine monohydrate supplementation on
the aerobic and anaerobic capacity of highly trained athletes.
J Sports Med Phys Fitness 2003, 43:64-68.
21. Eliason BC, Kruger J, Mark D, Rasmann DN: Dietary supplement
users: Demographics, product use, and medical system
interaction. J Am Board Fam Pract 1997, 10:265-271.
22. Groff JL, Gropper SS, Hunt SM: Advanced Nutrition and Human Metab-
olism 2nd edition. St. Paul, MN: West Publishing Company; 1995.
23. Kreider RB: Dietary supplements and the promotion of mus-
cle growth with resistance exercise. Sports Med 1999,
27:97-110.
24. Pittler Max H, Ernst Edzard: Dietary supplements for body-
weight reduction: a systematic review. Am J Clin Nutr 2004,
79(4):529-536.
25. Baxter , Jeffrey H 1, Mukerji , Pradip 1, Voss , Anne C 1, Tisdale ,
Michael J 2, Wheeler , Keith B: Attenuating Protein Degradation
and Enhancing Protein Synthesis in Skeletal Muscle in
Stressed Animal Model Systems. Medicine & Science in Sports &
Exercise 2006, 38(5 Supplement):S550-S551.
26. Smith HJ, Wyke SM, Tisdale MJ: Mechanism of the attenuation of
proteolysis-inducing factor stimulated protein degradation
in muscle by β-hydroxy-β-methylbutyrate. Cancer Res 2004,
64:8731-5.
27. Payne ET, Yasuda N, Bourgeois JM, Devries MC, Rodriguez MC, You-
suf J, Tarnopolsky MA: Nutritional therapy improves function
and complements corticosteroid intervention in mdx mice.
Muscle Nerve 2006, 33(1):66-77.
28. Nissen SL, Panton L, Wilhelm R, Fuller JC: Effect of β-hydroxy-β-
methylbutyrate (HMB) supplementation on strength and
body composition of trained and untrained males undergo-
ing intense resistance training. FASEB J 1996, 10:287.
29. Vukovich MD, Stubbs Nancy B, Bohlken Ruth M: Body Composi-
tion in 70-Year-Old Adults Responds to Dietary β-Hydroxy-
β-Methylbutyrate Similarly to That of Young Adults. J Nutr
2001, 131:2049-2052.
30. Van Koevering MT, Dolezal HG, Grill DR, Owens FN, Strasia CA,
Buchanan DS, Lake R, Nissen S: Effects of β-hydroxy β-methylbu-
tyrate on performance and carcass quality of feedlot steers.
J Anim Sci 1994, 72:1927-1935.
31. Nissen S, Sharp RL, Panton L, Vukovich M, Trappe S, Fuller JC Jr: β-
Hydroxy-β-Methylbutyrate (HMB) Supplementation in
Humans Is Safe and May Decrease Cardiovascular Risk Fac-
tors. Journal of Nutrition 2000, 130:1937-1945.
32. van Someren K, Edwards A, Howatson G: The effects of hmb sup-
plementation on indices of exercise-induced muscle damage
in man. Medicine & Science in Sports & Exercise 2003, 35(5):270.
33. Janssen GME, Kuipers H, Willems GM, Does RJMM, Janssen MPE,
Geurten P: Plasma activity of muscle enzymes: quantification
of skeletal muscle damage and relationship with metabolic
variables. Int J Sports Med 1989, 10(3):S160-S168.
34. Nuviala RJ, Roda L, Lapieza MG, Boned B, Giner A: Serum enzymes
activities at rest and after a marathon race. J Sports Med Phys
Fitness 1992, 32:180-186.
35. Baxter , Jeffrey H 1, Mukerji , Pradip 1, Voss , Anne C 1, Tisdale ,
Michael J 2, Wheeler , Keith B: Attenuating Protein Degradation
and Enhancing Protein Synthesis in Skeletal Muscle in
Stressed Animal Model Systems. Medicine & Science in Sports &
Exercise 2006, 38(5 Supplement):S550-S551.
36. Nissen SR, Sharp M, Ray JA, Rathmacher D, Rice JC, Fuller Jr, Con-
nelly AS, Abumrad N: Effect of leucine metabolite beta -
hydroxy-beta -methylbutyrate on muscle metabolism dur-
ing resistance-exercise training. J Appl Physiol 1996,
81:2095-2104.
37. van Someren K, Edwards A, Howatson G: Supplementation with
beta-hydroxy-beta-methylbutyrate (HMB) and alpha-ketoi-
socaproic acid (KIC) reduces signs and symptoms of exer-
cise-induced muscle damage in man. Int J Sport Nutr Exerc Metab
2005, 15(4):413-24.
38. Panton LB, Rathmacher JA, Baier S, Nissen S: Nutritional supple-
mentation of the leucine metabolite beta-hydroxy-beta-
methylbutyrate (hmb) during resistance training. Nutr 2000,
16(9):734-9.
39. Thomson JS: beta-Hydroxy-beta-Methylbutyrate (HMB) sup-
plementation of resistance trained men. Asia Pac J Clin Nutr
2004, 13(Suppl):
S59.
40. Neighbors KL, Ransone JW, Jacobson BH, LeFavi RG: Effects of die-
tary β-hydroxy-β-methylbutyrate on body composition in
collegiate football players. Med & Sci in Sports & Exerc 2000,
32:S60.
41. Nissen S, Sharp RL: Effect of dietary supplements on lean mass
and strength gains with resistance exercise: a meta-analysis.
J Appl Physiol 2003, 94:651-659.
42. Vukovich MD, Dreifort GD: Effect of β-Hydroxy β-Methylbu-
tyrate on the Onset of Blood Lactate Accumulation and
O2peak in Endurance-Trained Cyclists. The Journal of Strength
and Conditioning Research 2001, 15(4):491-497.
43. Vukovich Matthew D, Adams GD: Effect of β-hydroxy β-methyl-
butyrate (HMB) on vo2peak and maximal lactate in endur-
ance trained cyclists. Medicine & Science in Sports & Exercise 1997,
29(5):252.
44. Byrd PL, Mehta PM, DeVita PFACSM, Dyck D, Hickner RC: changes
in muscle soreness and strength following downhill running:
Nutrition & Metabolism 2008, 5:1 http://www.nutritionandmetabolism.com/content/5/1/1
Page 16 of 17
(page number not for citation purposes)
effects of creatine, hmb, and betagen supplementation. Med-
icine & Science in Sports & Exercise 1999, 31(5):263.
45. Flakoll P, Sharp R, Baier S, Levenhagen D, Carr C, Nissen S: Effect of
beta-hydroxy-beta-methylbutyrate, arginine, and lysine sup-
plementation on strength, functionality, body composition,
and protein metabolism in elderly women. Nutrition 2004,
20(5):445-51.
46. Vukovich , Stubbs NB, Bohlken RM, Desch MF, Fuller JC, Rathmacher
JA: The effect of dietary β-hydroxy-β-methylbutyrate (HMB)
on strength gains and body composition changes in older
adults [abstract]. FASEB J 1997, 11:A376.
47. Panton L, Rathmacher J, Fuller J, Gammon J, Cannon L, Stettler S, Nis-
sen S: Effect of β-hydroxy-β-methylbutyrate and resistance
training on strength and functional ability in the elderly. Med-
icine & Science in Sports & Exercise 1998, 30(5):194.
48. Soares JMC, Póvoas S, Neuparth MJ, Duarte JA: The effects of beta-
hydroxy-beta-methylbuturate (HMB) on muscle atrophy
induced by immobilization. Medicine & Science in Sports & Exercise
2001, 33(5):140.
49. Rathmacher JA: Effect of the leucine metabolite β-hydroxy-β-
methylbutyrate on muscle protein synthesis during pro-
longed bedrest. FASEB J 1999, 13:A1025.
50. Rathmacher JA, Zachwieja JJ, Smith SR, Lovejoy JL, Bray GA: The
effect of the leucine metabolite β-hydroxy-β-methylbutyrate
on lean body mass and muscle strength during prolonged
bedrest. FASEB J 1999, 13:A909.
51. Cohen DD: The effect of β-hydroxy-β-methylbutyrate (HMB)
and resistance training on changes in body composition dur-
ing positive and negative energy balance – a randomized
double-blind study. In MSc Thesis St. Bartholomew's and Royal
London School of Medicine and Dentistry – Queen Mary and West-
field College, University of London, London; 1997.
52. Coelho C, Carvalho : Effects of hmb supplementation on ldl-
cholesterol, strength and body composition of patients with
hypercholesterolemia. Medicine & Science in Sports & Exercise
2001, 33(5):M 340.
53. Sapir DG, Owen OE, Pozefsky T, Walser M: Nitrogen sparing
induced by a mixture of essential amino acids given chiefly as
their keto analogs during prolonged starvation in obese sub-
jects. J Clin Invest 1974, 54:974-980.
54. Tischler ME, Desautels M, Goldberg AL: Does leucine, Leucyl-
tRNA, or some metabolite of leucine regulate protein syn-
thesis and degradation in skeletal and cardiac muscle? J Biol
Chem 1982, 257:1613-1621.
55. Clark RH, Feleke G, Din M, Yasmin T, Singh G, Khan FA, Rathmacher
JA: Nutritional treatment for acquired immunodeficiency
virus-associated wasting using beta-hydroxy beta-methylbu-
tyrate, glutamine, and arginine: a randomized, double-blind,
placebo-controlled study. JPEN J Parenter Enteral Nutr 2000,
24(3):133-9.
56. May PE, Barber A, D'Olimpio JT, Hourihane A, Abumrad NN:
Reversal of cancer-related wasting using oral supplementa-
tion with a combination of beta-hydroxy-beta-methylbu-
tyrate, arginine, and glutamine. Am J Surg 2002, 183(4):471-9.
57. Alon T, Bagchi D, Preuss HG: Supplementing with beta-
hydroxy-beta-methylbutyrate (HMB) to build and maintain
muscle mass: a review. Res Commun Mol Pathol Pharmacol 2002,
111(1–4):139.
58. Cheng W, Phillips B, Abumrad N: Beta-hydroxy-beta-methyl
butyrate increases fatty acid oxidation by muscle cells. FASEB
J 1997, 11:A381.
59. Cheng W, Phillips B, Abumrad N: Effect of HMB on fuel utiliza-
tion, membrane stability and creatine kinase content of cul-
tured muscle cells. FASEB J 1998, 12:A950.
60. Ostaszewksi , Grzelkowska PK, Balasinska B, Barej W, Nissen S:
Effects of 3-hydroxy 3-methyl butyrate and 2-oxoisocaporate
on body composition and cholesterol metabolism in rabbits.
VII Symposium on Protein Metabolism and Nutrition 1995. Vale de
Santarim 162.
61. Ostaszewksi P, Kostiuk S, Balasinska B, Papet I, Glomot F, Nissen S:
The effects of 3-hydroxy 3-methyl butyrate (HMB) on mus-
cle protein synthesis and protein breakdown in chick and rat
muscle (Abstract). J Anim Sci 1996, 74:138.
62. Ostaszewski P, Kostiuk S, Balasinska B, Jank M, Papet I, Glomot F:
The leucine metabolite 3-hydroxy-3-methylbutyrate (HMB)
modifies protein turnover in muscles of the laboratory rats
and domestic chickens in vitro. J. Anim Physiol Anim Nutr 2000,
84:1-8.
63. Nissen SL, Panton L, Fuller J, Rice D, Ray M, Sharp R: Effect of feed-
ing β-hydroxy-β-methylbutyrate (HMB) on body composi-
tion and strength of women. FASEB J 1997, 11:A150.
64. Kreider RB, Ferreira M, Wilson M, Almada AL: Effects of calcium
β-hydroxy-β-methylbutyrate (HMB) supplementation during
resistance-training on markers of catabolism, body composi-
tion and strength. Int J Sports Med 1999, 20(8):503-9.
65. Slater G, Jenkins D, Logan P, Lee H, Vukovich M, Rathmacher JA,
Hahn AG: Beta-hydroxy-beta-methylbutyrate (HMB) supple-
mentation does not affect changes in strength or body com-
position during resistance training in trained men. Int J Sport
Nutr Exerc Metab 2001, 11(3):384-96.
66. Paddon-Jones D, Keech A, Jenkins D: Short-term beta-hydroxy-
beta-methylbutyrate supplementation does not reduce
symptoms of eccentric muscle damage. Int J Sport Nutr Exerc
Metab 2001, 11(4):442-50.
67. Hewitt Jennifer A, David Nunan, Glyn Howatson, van Someren , Ken
A, Whyte , Gregory P: HMB and KIC Supplementation Does
Not Reduce Signs and Symptoms of Exercise-Induced Mus-
cle Damage. Medicine & Science in Sports & Exercise 2006,
38(5):S401.
68. Ransone Jack, nNeighbors Kerri, Lefavi Robert, Chromiak Joseph:
The Effect of β-Hydroxy β-Methylbutyrate on Muscular
Strength and Body Composition in Collegiate Football Play-
ers. The Journal of Strength and Conditioning Research 2003,
17(1):34-39.
69. Hoffman Jay R, Cooper Joshua, Wendell Michael, Im Joohee, Kang Jie:
Effects of β-Hydroxy β-Methylbutyrate on Power Perform-
ance and Indices of Muscle Damage and Stress During High-
Intensity Training. The Journal of Strength and Conditioning Research
2004, 18(4):747-752.
70. Kreider RB, Ferreira M, Greenwood M, Wilson M, Grindstaff P, Plisk
S, Reinardy J, Cantler C, Almada AL: Effects of calcium B-HMB
supplementation during training on markers of catabolism,
body composition, strength and sprint performance.
Journal
of Exercise Physiology online 2000, 3(4):48-59.
71. Schmidt RA, Lee TL: Motor control and learning 3rd edition. Cham-
paign: Human Kinetics; 1999.
72. Wilson JM: Hull's Quantitative Equation on Human Perform-
ance. The Journal of Hyperplasia Research 2005, 5: [http://www.abc
bodybuilding.com/hull.pdf].
73. Weinberg R, Gould D: Foundations of Sport and Exercise Psychology:
Human Kinetics 2003.
74. Wilson GJ: The Effects of External Rewards on Intrinsic Moti-
vation. The Journal of Hyperplasia Research 2006, 6: [http://www.abc
bodybuilding.com/rewards.pdf].
75. Jones MV: Controlling emotions in sport. The Sport Psychologist
2003, 17:471-486.
76. Pyrczak F: Statistics with a Sense of Humor Second edition. Pyrczak Pub-
lishing; 1999.
77. Cohen J: The Statistical Power of Abnormal-Social Psycho-
logical Research: A Review. Journal of Abnormal and Social Psychol-
ogy 1962, 65(3):145-153.
78. Cohen J: Statistical Power Analysis for the Behavioral Sciences 2nd edition.
New York: Academic Press; 1988.
79. Bloomer Richard J, Goldfarb Allan H: Can nutritional supple-
ments reduce exercise-induced skeletal muscle damage?
Strength and Conditioning Journal 2003, 25(5):30-37.
80. Zatsiorsky VM, Kraemer WJ: Science and Practice of Strength Training
2nd edition. Champaign IL: Human Kinetics; 2006.
81. Nosaka K, Sakamoto K, Newton M, Sacco P: The repeated bout
effect of reduced-load eccentric exercise on elbow flexor
muscle damage. Eur J Appl Physiol 2001, 85(1–2):34-40.
82. Proteau L, Marteniuk RG, Levesque L: A sensorimotor basis for
motor learning: Evidence indicating specificity of practice.
Quarterly Journal of Experimental Psychology 1992, 44A:557-575.
83. Fleck SJ, Kraemer WJ: Designing Resistance Training Programs 3rd edi-
tion. Champaign, IL: Human Kinetics; 2004.
84. Wilson J, Wilson G: The Specificity Hypothesis–A Critical
Review. The Journal of Hyperplasia Research 2005, 5: [http://
www.abcbodybuilding.com/specificityindex.php].
85. Rivenes R, Sawyer D: The specificity of motor performance:
Reexamination of the Fleishman data. Int Sports J 1999, 3:22-29.
Nutrition & Metabolism 2008, 5:1 http://www.nutritionandmetabolism.com/content/5/1/1
Page 17 of 17
(page number not for citation purposes)
86. Schott J, McCully K, Rutherford OM: The role of metabolites in
strength training. II. Short versus long isometric contrac-
tions. Eur J Appl Physiol Occup Physiol 1995, 71(4):337-41.
87. Bray SR, Widmeyer WN: Athletes' perceptions of the home
advantage: An investigation of perceived causal factors. Jour-
nal of Sport Behavior 2000, 23:1-10.
88. Slater , Gary , Jenkins J, David : Beta-Hydroxy-beta-Methylbu-
tyrate (HMB) Supplementation and the Promotion of Mus-
cle Growth and Strength. Sports Medicine 2000, 30(2):105-116.
89. Décombaz Jacques, Bury Alexandre, Hager Corinne, Nissen Steven L,
Sharp Rick L: HMB meta-analysis and the clustering of data
sources. J Appl Physiol 2003, 95:2180-2182.
90. ISSA: The Truth about HMB. 2005 [http://www.bodybuild
ing.com/fun/issa73.htm].
91. Phillips B: Sports Supplement Review. Golden, CO: Mile High;
1997.
92. Dohm GL: Protein nutrition for the athlete. Clin Sports Med
1984, 3:595-604.
93. Gallagher PM, Carrithers JA, Goodard MP, Schulze KE, Trappe SW:
β-Hydroxy-β-methylbutyrate ingestion, Part II: Effects on
hematology, hepatic and renal function. Med Sci Sports Exerc
2000, 32:2116-2119.
94. Nissen SL, Abumrad N: Nutritional role of the leucine metabo-
lite β-hydroxy-β-methylbutyrate (HMB). J Nutr Biochem 1997,
8:300-311.
95. Nissen S, Faidley TD, Zimmerman DR, Izard R, Fisher CT: Colostral
milk fat percentage and pig performance are enhanced by
feeding the leucine metabolite β-hydroxy β-methylbutyrate
to sows. J Anim Sci 1994, 72:2332-2337.
96. Nissen S, Fuller JC Jr, Sell J, Ferket PR, Rives DV: The effect of β-
hydroxy-β-methylbutyrate on growth, mortality and carcass
qualities of broiler chickens. Poult Sci 1994, 73:137-155.
97. Peterson AL, Qureshi MA, Ferket PR, Fuller JC Jr: Enhancement of
cellular and humoral immunity in young broilers by the die-
tary supplementation of β-hydroxy-β-methylbutyrate. Immu-
nopharm Immunotoxicol 1999, 21(2):307-330.
98. Peterson AL, Qureshi MA, Ferket PR, Fuller JC Jr: In vitro exposure
with beta-hydroxy-beta-methylbutyrate enhances chicken
macrophage growth and function. Vet Immunol Immunopathol
1999, 4;67(1):67-78.
99. Nissen S, Morrical D, Fuller JC Jr: The effects of the leucine cat-
abolite β-hydroxy-β-methylbuyrate on the growth and
health of growing lambs.
J Anim Sci 1994, 77:243.
100. Vukovich MD, Slater G, Macchi MB, Turner MJ, Fallon K, Boston T,
Rathmacher J: beta-hydroxy-beta-methylbutyrate (HMB)
kinetics and the influence of glucose ingestion in humans. J
Nutr Biochem 2001, 12(11):631-639.
101. Smith HJ, Mukerji P, Tisdale MJ: Attenuation of proteasome-
induced proteolysis in skeletal muscle by β-hydroxy-β-meth-
ylbutyrate in cancer-induced muscle loss. Cancer Res 2005,
65:277-83.
102. Bachhawat BK, Robinson WG, Coon MJ: Enzymatic carboxyla-
tion of beta-hydroxyisovaleryl coenzyme A. J Biol Chem 1956,
219:539-550.
103. Bastiaanse EM, Hold KM, Van der Laarse A: The effect of mem-
brane cholesterol content on ion transport processes in
plasma membranes. Cardiovasc Res 1997, 33:272-283.
104. Pierno S, De Luca A, Tricarico D, Roselli A, Natuzzi F, Ferrannini E,
Laico M, Camerino DC: Potential risk of myopathy by HMG-
CoA reductase inhibitors: a comparison of pravastatin and
simvastatin effects on membrane electrical properties of rat
skeletal muscle fibers. J Pharmacol Exp Ther 1995, 275:1490-1496.
105. Mutoh T, Kumano T, Nakagawa H, Kuriyama M: Role of tyrosine
phosphorylation of phospholipase C gamma1 in the signaling
pathway of HMG-CoA reductase inhibitor-induced cell
death of L6 myoblasts. FEBS Lett 1999, 446:91-94.
106. Ditscheid B, Keller S, Jahreis G: Cholesterol metabolism is
affected by calcium phosphate supplementation in humans.
J Nutr 2005, 135(7):1678-82.
107. Soma MR, Corsini A, Paoletti R: Cholesterol and mevalonic acid
modulation in cell metabolism and multiplication. Toxicol Lett
1992, 64–65(Spec No):1-15.
108. Evans M, Rees A: Effects of HMG-CoA reductase inhibitors on
skeletal muscle: are all statins the same? Drug Safety 2005,
25:649-663.
109. Miles L, Miles MV, Tang PH, Horn PS, Wong BL, DeGrauw TJ, More-
hart PJ, Bove KE: Muscle coenzyme Q: a potential test for
mitochondrial activity and redox status. Pediatr Neurol 2005,
32(5):318-24.
110. Glickman MH, Ciechanover A: The ubiquitin-proteasome prote-
olytic pathway: destruction for the sake of construction. Phys-
iol Rev 2002, 82:373-428.
111. Bartoli M, Richard I: Calpains in muscle wasting. Int J Biochem Cell
Biol 2005, 37(10):2115-33.
112. Whitehouse AS, Khal J, Tisdale MJ: Induction of protein catabo-
lism in myotubes by 15(S)-hydroxyeicosatetraenoic acid
through increased expression of the ubiquitin-proteasome
pathway. Br J Cancer 2003, 21(2):155-67.
113. Whitehouse AS, Tisdale MJ: Downregulation of ubiquitin-
dependent proteolysis by eicosapentaenoic acid in acute
starvation. Biochem Biophys Res Commun 2001, 285:598-602.
114. Riley DA, Ilyina-Kakueva EI, Ellis S, Bain JL, Slocum GR, Sedlak FR:
Skeletal muscle fiber, nerve, and blood vessel breakdown in
space-flown rats. FASEB J 1999, 4:84-91.
115. Day MK, Allen DL, Mohajerani L, Greenisen MC, Roy RR, Edgerton
VR: Adaptations of human skeletal muscle fibers to space-
flight. J Gravit Physiol 1995, 2:47-50.
116. Bodine SC, Latres E, Baumhueter S, Lai VKM, Nunez L, Clarke BA,
Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valen-
zuela DM, DeChiara TM, Stitt TM, Yancopoulos GD, Glass DJ: Iden-
tification of ubiquitin ligases required for skeletal muscle
atrophy. Science 2001, 294:1704-1708.
117. Reid MD: Response of the ubiquitin-proteasome pathway to
changes in muscle activity. Am J Physiol Regul Integr Comp Physiol
2005, 288(6):R1423-31.
118. Sonna LA, Wenger CB, Flinn S, Sheldon HK, Sawka MN, Lilly CM:
Exertional heat injury and gene expression changes: a DNA
microarray analysis study. J Appl Physiol 2004, 96:1943-1953.
119. Thompson HS, Scordalis SP: Ubiquitin changes in human biceps
muscle following exercise-induced damage. Biochem Biophys
Res Commun 1994, 204:1193-1198.
120. Anthony JC, Anthony TG, Kimball SR, Jefferson LS:
Signaling path-
ways involved in translational control of protein synthesis in
skeletal muscle by leucine. J Nutr 2001, 131:856S-60S.
121. Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR:
A high proportion of leucine is required for optimal stimula-
tion of the rate of muscle protein synthesis by essential
amino acids in the elderly. Am J Physiol Endocrinol Metab 2006,
291(2):E381-E387.
122. Norton LE, Layman DK: Leucine regulates translation initiation
of protein synthesis in skeletal muscle after exercise. J Nutr
2006, 136(2):533S-537S.
123. Willoughby DS, Taylor M, Taylor L: Glucocorticoid receptor and
ubiquitin expression after repeated eccentric exercise. Med
Sci Sports Exerc 2003, 35:2023-2031.
124. Toledo FG, Watkins S, Kelley DE: Changes induced by physical
activity and weight loss in the morphology of inter-myofibril-
lar mitochondria in obese men and women. J Clin Endocrinol
Metab 2006, 92(5):1827-1833.
125. Anonymous: Supplement Review – Calcium. The Journal of
Hyperplasia Research 2003, 3: [http://www.abcbodybuilding.com/cal
cium.pdf].
126. Nonnecke BJ, Franklin ST, Nissen SL: Leucine and its catabolites
alter mitogen-stimulated DNA synthesis by bovine lym-
phocytes. J Nutr 1991, 121:1665-1672.
127. Rao RD, Buckner JC, Sarkaria JN: Mammalian target of rapamy-
cin (mTOR) inhibitors as anti-cancer agents. Curr Cancer Drug
Targets 2004, 4(8):621-35.
128. Biolo G, Tipton KD, Klein S, Wolfe RR: An abundant supply of
amino acids enhances the metabolic effect of exercise on
muscle protein. Am J Physiol 1997, 273:E122-9.
129. Tipton KD, Rasmussen BB, Miller SL, Wolf SE, Owens-Stovall SK,
Petrini BE, Wolfe RR: Timing of amino acid-carbohydrate
ingestion alters anabolic response of muscle to resistance
exercise. Am J Physiol Endocrinol Metab 2001, 281:E197-E206.
... The results of our meta-analysis, conducted on 10 RCTs with a total of 421 (intervention group: 227, control group: 194) adult participants, revealed no beneficial effects of HMB supplementation on TC (WMD: In recent years, HMB has been used as one of the nutritional supplements used by athletes to adjust homeostasis and increase lipolysis and fat-free mass. Several studies have shown that supplementation with HMB alters cholesterol synthesis in the liver by converting it to HMG-CoA (9,(38)(39)(40). Different studies have been performed on the effects of HBM on weight loss, lipid profile, and muscle strength. ...
... However, it is acknowledged that not all studies could perfectly control for dietary habits, and this represents a limitation of the review. Further, it is suggested that future studies should include more rigorous dietary controls more precisely to account for such variables (40). ...
... HMB supplementation is known to stimulate muscle protein synthesis. Increased muscle mass is often associated with a higher metabolic rate, potentially leading to favorable changes in lipid profiles (40). Additionally, HMB might influence inflammatory markers, which are linked to cardiovascular health and cholesterol regulation (44). ...
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Background and aim The regulation of lipid metabolism is crucial for preventing cardiovascular diseases, which are among the leading causes of mortality worldwide. β-hydroxy-β-methylbutyrate (HMB) has garnered attention for its potential role in modulating lipid profiles. However, the magnitude of these effects are unclear due to the heterogeneity of the studies. This study aimed to provide a comprehensive overview of the randomized controlled trials (RCTs) that have examined the effects of HMB on lipid profiles in adults. Methods Databases including PubMed, Web of Science, and Scopus, were searched for relevant studies through January 2024. The study protocol was also registered at Prospero (no. CRD42024528549). Based on a random-effects model, we calculated WMDs and 95% confidence intervals (CIs). The outcomes assessed included total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Sensitivity, subgroup and meta-regression analyses were also conducted. Results Our analysis included a total of 10 RCTs comprising 421 participants. The pooled data revealed no significant effect of HMB supplementation on TC (WMD: −2.26 mg/dL; 95%CI: −6.11 to 1.58; p = 0.25), TG (WMD: −2.83 mg/dL 95% CI: −12.93 to 7.27; p = 0.58), LDL-C (WMD: 0.13 mg/dL; 95%CI: −3.02 to 3.28; mg; p = 0.94), and HDL-C (WMD: −0.78 mg/dL; 95%CI: −2.04 to 0.48; p = 0.22). The quality of evidence was rated as moderate to low for all outcomes. Conclusion The current evidence from RCTs suggests that HMB supplementation does not significantly alter lipid profiles, including TC, TG, LDL-C, and HDL-C. Further research is warranted to confirm these results and explore the potential mechanisms of action of HMB. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=528549, CRD42024528549.
... HMB may be particularly beneficial for populations prone to muscle loss, such as the elderly or individuals with chronic diseases. Athletes interested in optimizing muscle recovery and growth may consider incorporating HMB into their supplementation regimen, especially during periods of intense training [20]. ...
... In combination with resistance training, some studies suggest that HMB (3 g/day) supplementation may help to counteract muscle loss in the elderly. (Wilson et al., 2008;Vukovich et al., 2001;Yang et al., 2023). Recent systematic reviews conclude that HMB improves lean muscle mass and preserves muscle strength and function in older people with sarcopenia or frailty (Costa Riela et al., 2021;Oktaviana et al., 2019;Rossi et al., 2017). ...
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Function declines throughout life although phenotypical manifestations in terms of frailty or disability are only seen in the later periods of our life. The causes underlying lifelong function decline are the aging process "per se", chronic diseases, and lifestyle factors. These three etiological causes result in the deterioration of several organs and systems which act synergistically to finally produce frailty and disability. Regardless of the causes, the skeletal muscle is the main organ affected by developing sarcopenia. In the first section of the manuscript, as an introduction, we review the quantitative and qualitative age-associated skeletal muscle changes leading to frailty and sarcopenia and their impact in the quality of life and independence in the elderly. The reversibility of frailty and sarcopenia are discussed in the second and third sections of the manuscript. The most effective intervention to delay and even reverse frailty is exercise training. We review the role of different training programs (resistance exercise, cardiorespiratory exercise, multicomponent exercise, and real-life interventions) not only as a preventive but also as a therapeutical strategy to promote healthy aging. We also devote a section in the text to the sexual dimorphic effects of exercise training interventions in aging. How to optimize the skeletal muscle anabolic response to exercise training with nutrition is also discussed in our manuscript. The concept of anabolic resistance and the evidence of the role of high-quality protein, essential amino acids, creatine, vitamin D, β-hydroxy-β-methylbutyrate, and Omega-3 fatty acids, is reviewed. In the last section of the manuscript, the main genetic interventions to promote robustness in preclinical models are discussed. We aim to highlight the molecular pathways that are involved in frailty and sarcopenia. The possibility to effectively target these signaling pathways in clinical practice to delay muscle aging is also discussed.
... HMB may be particularly beneficial for populations prone to muscle loss, such as the elderly or individuals with chronic diseases. Athletes interested in optimizing muscle recovery and growth may consider incorporating HMB into their supplementation regimen, especially during periods of intense training [20]. ...
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This work is licensed under Creative Commons Attribution 4.0 License APPR.MS.ID.000592. Abstract Nutraceuticals are gaining recognition for their preventive and therapeutic roles in complex diseases. This review explores the potential of nutraceuticals in various health conditions, with a particular focus on their relevance in high-altitude environments. The review explores specific nutraceutical sources like Ophiocordyceps sinensis and Spirogyra portcallis, highlighting their rich bioactive compound profiles and potential health benefits. The review also examines the significance of wild edible fruit plants of the Indian Himalayan region as a source of essential nutrients and antioxidants. Furthermore, it explores the application of nutraceuticals in sports, emphasizing their role in enhancing performance, recovery, and overall health. It details various categories of sports nutraceuticals, including organic fat burners, muscle building supplements, and substances that aid in mitigating gastrointestinal issues. Finally, the review discusses the potential of nutraceuticals like Berberine, Curcumin, Green tea, etc in promoting gut health and modulating gut microbiota. Overall, the review underscores the promising potential of nutraceuticals as a valuable addition to conventional healthcare approaches.
... For example, DHEA, a precursor of sex steroid hormones, promotes protein synthesis and anabolism, resulting in increased muscle mass and strength [30]. Beta-methyl-hydroxy-beta-methylbutyrate has demonstrated efficacy in preserving muscle mass and strength in older individuals and promoting skeletal muscle hypertrophy in bodybuilders and strength/power athletes [31,32]. Creatine has also been reported to positively affect several aspects of exercise performance, including muscle mass and strength, glycogen synthesis, and aerobic capacity [33]. ...
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... In addition to its cellular metabolic function, leucine and its breakdown product, 3,3-hydroxymethylbutyrate (HMB), are frequently used as dietary supplements to increase muscle building and exercise endurance and performance, as well as in elderly patients with sarcopenia or type 2 diabetes [8][9][10] . In humans, under normal physiological conditions, approximately 5% of leucine is metabolized into HMB 11 . While both metabolites are generally well tolerated, their effects on physiology have not been comprehensively studied 12 . ...
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In humans, defects in leucine catabolism cause a variety of inborn errors in metabolism. Here, we use Caenorhabditis elegans to investigate the impact of mutations in mccc-1, an enzyme that functions in leucine breakdown. Through untargeted metabolomic and transcriptomic analyses we find extensive metabolic rewiring that helps to detoxify leucine breakdown intermediates via conversion into previously undescribed metabolites and to synthesize mevalonate, an essential metabolite. We also find that the leucine breakdown product 3,3-hydroxymethylbutyrate (HMB), commonly used as a human muscle-building supplement, is toxic to C. elegans and that bacteria modulate this toxicity. Unbiased genetic screens revealed interactions between the host and microbe, where components of bacterial pyrimidine biosynthesis mitigate HMB toxicity. Finally, upregulated ketone body metabolism genes in mccc-1 mutants provide an alternative route for biosynthesis of the mevalonate precursor 3-hydroxy-3-methylglutaryl-CoA. Our work demonstrates that a complex host–bacteria interplay rewires metabolism to allow host survival when leucine catabolism is perturbed.
... For example, DHEA, a precursor of sex steroid hormones, promotes protein synthesis and anabolism, resulting in increased muscle mass and strength [29]. Beta-methyl-hydroxy-beta-methylbutyrate has demonstrated efficacy in preserving muscle mass and strength in older individuals and promoting skeletal muscle hypertrophy in bodybuilders and strength/power athletes [30,31]. Creatine has also been reported to positively affect several aspects of exercise performance, including muscle mass and strength, glycogen synthesis, and aerobic capacity [32]. ...
Preprint
Full-text available
Sialyllactose (SL) is a functional human milk oligosaccharide essential for immune support, brain development, intestinal maturation, and antiviral defense. However, despite its established health benefits, the effect of SL on exercise performance and muscle mass in mice remains unknown. Here, we aimed to investigate, for the first time, the effects of 6′-SL on muscle functions. Seven-week-old male C57BL/6J mice were administered 100 mg/kg 6′-SL for 12 weeks, after which exhaustive treadmill performance, muscle strength, and muscle phenotype were examined. The administration of 6′-SL significantly improved exhaustive treadmill performance metrics, including distance and exhaustion time. Grip strength was also increased by 6′-SL administration. Additionally, 6′-SL increased muscle mass in both the gastrocnemius (GAS) and soleus. 6′-SL administration led to an increase in the minimum Feret’s diameter and the protein expression of total myosin heavy chain in the GAS muscle. In conclusion, 6′-SL administration in vivo led to increased running distance and time by increasing muscle mass and strength. These findings collectively indicate that 6′-SL is a potential agent for improving muscle health and exercise performance.
... As a supplement, HMB may affect inflammatory cascades and, due to the anabolic effect (mTOR pathway), modulate protein metabolism [65]. So far, many studies have shown that HMB supplementation can increase lean body mass with reduced markers of muscle damage [66]. HMB supplements have been proven to preserve muscle mass during 10 days of bed rest in older people [67]. ...
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The study aimed to show the potential clinical application of supplements used among sportsmen for patients suffering from Intensive Care Unit-acquired Weakness (ICUAW) treatment. ICUAW is a common complication affecting approximately 40% of critically ill patients, often leading to long-term functional disability. ICUAW comprises critical illness polyneuropathy, critical illness myopathy, or a combination of both, such as critical illness polyneuromyopathy. Muscle degeneration begins shortly after the initiation of mechanical ventilation and persists post-ICU discharge until proteolysis and autophagy processes normalize. Several factors, including prolonged bedrest and muscle electrical silencing, contribute to muscle weakness, resulting from an imbalance between protein degradation and synthesis. ICUAW is associated with tissue hypoxia, oxidative stress, insulin resistance, reduced glucose uptake, lower adenosine triphosphate (ATP) formation, mitochondrial dysfunction, and increased free-radical production. Several well-studied dietary supplements and pharmaceuticals commonly used by athletes are proven to prevent the aforementioned mechanisms or aid in muscle building, regeneration, and maintenance. While there is no standardized treatment to prevent the occurrence of ICUAW, nutritional interventions have demonstrated the potential for its mitigation. The use of ergogenic substances, popular among muscle-building sociates, may offer potential benefits in preventing muscle loss and aiding recovery based on their work mechanisms.
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Background Parenteral nutrition (PN) without enteral nutrition (EN) leads to marked atrophy of gut‐associated lymphoid tissue (GALT), causing mucosal defense failure in both the gut and the extraintestinal mucosal system. We evaluated the effects of beta‐hydroxy‐beta‐methylbutyrate (HMB) on GALT and gut morphology in PN‐fed mice. Methods Experiment 1: male Institute of Cancer Research mice were assigned to the Chow ( n = 12), Control (standard PN: n = 10), or H600 and H2000 (PN containing 600 mg/kg or H2000 mg/kg body weight of Ca‐HMB: n = 12 and 10, respectively) groups. After 5 days of dietary manipulation, all mice were killed and the whole small intestine was harvested. GALT lymphocyte cell numbers and phenotypes of Peyer patch (PP), intraepithelial space, and lamina propria lymphocytes were evaluated. Experiment 2: 47 mice (Chow: n = 12; Control: n = 14; H600: n = 11; and H2000: n = 10) were fed for 5 days as in experiment 1. Proliferation and apoptosis of gut immune cells and mucosa, and protein expressions (mammalian target of rapamycin [mTOR], caspase‐3, and Bcl2) were evaluated in the small intestine. Results Compared with the Controls, the Chow and HMB groups showed significantly higher PP cell numbers, prevented gut mucosal atrophy, inhibited apoptosis of gut cells, and increased their proliferation in association with increased mTOR activity and Bcl2 expression. Conclusion HMB‐supplemented PN is a potentially novel method of preserving GALT mass and gut morphology in the absence of EN.
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Calcium β-hydroxy β-methylbutyrate (HMB) supplementation has been reported to reduce catabolism and promote gains in strength and fat free mass in untrained individuals initiating training. However, the effects of HMB supplementation on strength and body composition alterations during training in athletes is less clear. This study examined the effects of 28-d of calcium HMB supplementation during intense training on markers of catabolism, body composition, strength, and sprint performance. In a double-blind and randomized manner, 28 NCAA division I-A football players were matched-paired and assigned to supplement their diet for 28-d during winter resistance/agility training (~8 hr/wk) with a carbohydrate placebo supplement (P) or the P supplement with 3 g/day of HMB as a calcium salt (HMB). Prior to and following supplementation: dietary records and fasting blood samples were obtained; body composition was determined via DEXA; subjects performed maximal effort bench press, barbell back squat, and power clean isotonic repetition tests; and, subjects performed a repeated cycle ergometer sprint test (12 x 6-s sprints with 30-s rest recovery) to simulate a 12-play drive in football. Results revealed no significant differences between the placebo and HMB supplemented groups in markers of catabolism, muscle/liver enzyme efflux, hematological parameters, body composition, combined lifting volume, or repetitive sprint performance. Results indicate that HMB supplementation (3 g/day) during off-season college football resistance/agility training does not reduce catabolism or provide ergogenic benefit.
Book
Designing Resistance Training Programs, Fourth Edition, is a guide to developing individualized training programs for both serious athletes and fitness enthusiasts. Two of the world’s leading experts on strength training explore how to design scientifically based resistance training programs, modify and adapt programs to meet the needs of special populations, and apply the elements of program design in the real world. The fourth edition presents the most current information while retaining the studies that are the basis for concepts, guidelines, and applications in resistance training. Meticulously updated and heavily referenced, the fourth edition contains the following updates: A full-color interior provides stronger visual appeal.Sidebars focus on a specific practical question or an applied research concept, allowing readers to connect research to real-life situations.Multiple detailed tables summarize research from the text, offering an easy way to compare data and conclusions.A glossary makes it simple to find key terms in one convenient location.Newly added instructor ancillaries make the fourth edition a true learning resource for the classroom (available at www.HumanKinetics.com/DesigningResistanceTrainingPrograms). Designing Resistance Training Programs, Fourth Edition, is an essential resource for understanding and applying the science behind resistance training for any population.
Conference Paper
High-performance physical activity and postexercise recovery lead to significant changes in amino acid and protein metabolism in skeletal muscle. Central to these changes is an increase in the metabolism of the BCAA leucine. During exercise, muscle protein synthesis decreases together with a net increase in protein degradation and stimulation of BCAA oxidation. The decrease in protein synthesis is associated with inhibition of translation initiation factors 4E and 4G and ribosomal protein S6 under regulatory controls of intracellular insulin signaling and leucine concentrations. BCAA oxidation increases through activation of the branched-chain a-keto acid dehydrogenase (BCKDH). BCKDH activity increases with exercise, reducing plasma and intracellular leucine concentrations. After exercise, recovery of muscle protein synthesis requires dietary protein or BCAA to increase tissue levels of leucine in order to release the inhibition of the initiation factor 4 complex through activation of the protein kinase mammalian target of rapamycin (mTOR). Leucine's effect on mTOR is synergistic with insulin via the phosphoinositol 3-kinase signaling pathway. Together, insulin and leucine allow skeletal muscle to coordinate protein synthesis with physiclogical state and dietary intake.
Conference Paper
Studies both in vivo and in vitro have shown that leucine at a very high dose can stimulate muscle protein synthesis, an effect that is enhanced in vivo by insulin secreted in response to the leucine dose. High leucine can also inhibit protein degradation in skeletal muscle, as well as in liver. In contrast, at normal physiological levels, increasing leucine concentration by infusion stimulates muscle protein synthesis by enhancing its sensitivity to insulin. It is concluded that the role of leucine in vivo is to provide a signal that amino acids are available, which in combination with the signal of energy availability from insulin, stimulates muscle protein synthesis.
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The leucine metabolite beta-hydroxy-beta-methyl butyrate (HMB) enhances the effect of exercise in increasing fat-free muscle mass in humans (Nissen et al., J. Appl. Physiol. 81: 2095-2104, 1996). we examined its effect on fatty acid (FA) utilization by two muscle cell lines, rat heart H9C2 and mouse skeletal C2C12 cells. H9C2 and C2C12 myoblasts were differentiated in culture into myotubes and were exposed for 48 hours to 0, 6 and 12 mM HMB. The cells were then washed and assayed for uptake, lipid-incorporation and oxidation of 3H-oleate. Oxidation was quantitated from tritium released as water after medium treatment with trichloroacetic acid and passage on a Dowexresin. Uptake was estimated from cell-associated tritium and FA incorporation into lipids from chromatography of cell extracts on silica G (hexane:diethyl ether:acetic acid, 80:20:1). HMB treatment did not alter cell protein or cell DNA per dish. Similarly, it did not affect oleate uptake or its incorporation into phospholipids, triglycerides and cholesteryl esters. In contrast, HMB increased the tritium released into the medium by 25 and 30 percents for heart and skeletal muscle cells, respectively (p<0.005). The increase was observed following removal of HMB and may have reflected a change in capacity of FA-oxidative enzymes or in levels of critical cellular substrates or cofactors. This HMB-induced increase may provide the muscle cell with an oxidative advantage during exercise and could account for some of the decrease in muscle fat observed with HMB intake in humans.
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Beta-hydroxy beta-methyl-butyrate (HMB) enhances the gains in muscle strength and lean mass associated with resistance training (J Nutr Biochem, 1997; 8:300-311). To study the underlying mechanism for this action, myoblasts from two cell lines, H9C2 and C2C12, derived, respectively, from heart and skeletal muscles, were differentiated in culture to myotubes and exposed (2 to 4 days) to 0-6 mM HMB. The following parameters were examined; beta-oxidation of palmitate, medium content of lactate dehydrogenase (LDH) and creatine kinase (CK) activity of cell homogenates. HMB treatment increased beta-oxidation of palmitate by 30% (P<0.001). It decreased LDH release from myotubes by 25% (p<0.05). Inclusion of HMB in the differentiation medium also increased cellular expression of CK by 25% (p<0.01). The data suggest that HMB exerts several effects on muscle cells. 1) it increases the cell's oxidative capacity. This action outlasts HMB removal from the culture medium and might involve changes in oxidative enzymes. Increased fat oxidation by muscle may contribute to gains in lean body mass. 2) HMB appears to exert a "stabilizing" effect on myotube membranes as evidenced by the decrease in LDH leak into the medium. This effect may be particularly beneficial during strength training as it would protect against some of the associated cellular injury. Finally, the effect of HMB on cellular CK, an established differentiation marker, suggests that it might enhance expression of muscle-specific proteins.
Article
Supplementing the diet of men engaged in resistance training with the leucine metabolite HMB can increase lean tissue gains by slowing muscle proteolysis. To determine if this same effect occurs in women a preliminary study was carried out in 36 non-exercising women (Exp 1) who were given supplements of either a placebo or 3 g of HMB (calcium salt) daily. Body composition was measured by TOBEC before and after 4 wk of treatment. In a second study, 37 women (Exp 2) were also supplemented with a placebo or 3 g of HMB per day combined with a supervised 3X/wk weight training protocol. Body composition was measured at the beginning and after 4 wk by underwater weighing (UWW). Placebo HMB 4-wk net Sig Exp. 1: No exercise Δ lean (kg, TOBEC) 0.06 0.09 0.03 ns Δ fat (kg, TOBEC) 0.04 0.02 -0.02 ns Exp. 2: + Exercise Δ lean (kg, UWW) 0.37 0.85 0.48 p<.05 Δ fat (kg, UWW) -0.08 -0.22 -0.14 ns Δ Bench press 9.0% 16.0% 7.0% p<.05 HMB did not alter blood chemistry, blood hematology or clinical measures of well being in either study. Combined with weight training HMB increased lean gain and strength in women, while in sedentary women there was no effect. This differential effect of HMB on lean mass between Exp 1 and Exp 2 suggests endogenous production of HMB from leucine may not be adequate to meet the needs of muscles during vigorous weight training.