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Role of HMB in cancer cachexia

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Journal of Nutritional Oncology, February 15, 2019, Volume 4, Number 1 ·1 ·

Role of β-Hydroxy β-Methylbutyrate (HMB) in Cancer Cachexia/

Sarcopenia
Hana Ajouz1, Amaury Martinez Garcia2, Adrian Barbul3*
1Department of Surgery, New York University School of Medicine, New York, NY 1001657; 2Department of Surgery, Bronx Lebanon
Hospital, Bronx, NY 10457; 3Department of Surgery, Vanderbilt University School of Medicine and the Tennessee Valley Healthcare
System, Nashville, TN 37212-2637, USA

Abstract: Cancer cachexia is a complex multifactorial syndrome that has a substantial impact on the quality of life
of cancer patients. Although some treatment options exist to counteract cachexia, very few options counteract
sarcopenia (loss of muscle mass). HMB may be a viable component in multi-modal approaches targeting treatment of
cancer cachexia/sarcopenia. Evidence suggests that HMB promotes myogenic events, suppresses proteasome activity,
and activates protein synthesis. HMB also represses inflammation, reduces tumor growth, and increases lifespan.
Key words: Cachexia; Cancer; Sarcopenia; β-hydroxyl-β-methylbutyrate (HMB)

Introduction development, but none are currently approved for this

It is estimated that half of all patients with cancer
eventually develop cachexia[1], a complex multifactorial
syndrome associated that is also associated with other
medical conditions [1]. The exact incidence of cachexia
varies by tumor type, the highest incidence being
observed in gastric and pancreatic cancer (more than
80%) [2]. Cachexia has a significant negative impact on
the patient’s quality of life, being associated with poor
responses to chemotherapy and decreased survival [3,4].
It is believed that cachexia is indirectly responsible for
the death of approximately 20% of cancer patients [4].
Cachexia is characterized by systemic inflame-
mation, negative protein balance, and an involuntary
loss of lean body mass (sarcopenia), with or without
wasting of adipose tissue. Muscle mass loss (sarcopenia)
occurs more rapidly and extensively in cancer patients
[5]. Sarcopenia occurs in skeletal and cardiac muscle
masses, but the muscle content of other visceral organs
is preserved [6]. Like cachexia, sarcopenia has also been
noted to be a direct predicator of outcome in cancer
patients.
Although the ideal strategy to manage cancer
cachexia is to treat and/or reverse the underlying cancer,
this is all too often unachievable. Another alternative is
to identify therapies effective in counteracting or
preferably preventing cachexia/sarcopenia. Many
nutritional and pharmacological interventions have been
studied in this regard. Several promising
pharmacological agents are in various stages of
Corresponding author: Adrian Barbul, MD, Division of
General Surgery, Vanderbilt University School of Medicine,
1161 21st Avenue South, D-5203 Medical Center North,
Nashville, TN, USA; Tel: +01 372 322 577; +01 615 343
5613; Fax: +01 615 343 9485; Email: adrian.barbul@vander-
bilt.edu
specific use. In regards to nutritional agents, one
limiting factor is that most reverse body weight losses
by increasing fat mass and/or water retention without
restoring muscle mass [7]. Thus few viable options exist
for the cachexic cancer patient, who is often treated by a
health care system that is not well equipped to deal this
condition.
Herein we examine critically the possible role of β-
Hydroxy β-Methylbutyrate (HMB) as a nutritional agent
to counteract cancer cachexia. HMB promotes myogenic
events, suppresses proteasome activity, and activates
protein synthesis and skeletal muscle growth. We
provide an overview of the multiple mechanisms that are
involved in the development of cancer cachexia and then
discuss the ability of HMB to counteract several of these
pathophysiologic mechanisms and examine whether
HMB can be an effective adjuvant in a multi-modal
therapeutic approach targeting cancer cachexia. We will
also examine the use HMB, prophylactically, before
cachexia occurs in high risk patients.
Mechanisms of Cancer Cachexia
Several mechanisms have been implicated in the
development of cancer cachexia. We are presenting the
main pathways, although it should be noted that
significant cross-over exists among them. We will
discuss also the possible therapeutic effects of HMB in
each of these instances.
Inflammatory Mediators
Cancer cachexia is an inflammation-induced
physiological and metabolic response which transfers
amino acids from muscle catabolism into the amino acid
pool required for acute phase reaction protein synthesis
[8,9]. Increased pro-inflammatory cytokine activity, as
part of systematic inflammation, is a hallmark of cancer
·2 ·
cachexia [10]. Cytokines such as tumor necrosis factor-α
(TNF-α), interleukin-6 (IL-6), interleukin-1 (IL-1), and
interferon-gamma (IFN-ɣ) appear to mediate many
responses observed [7]. Pro-inflammatory and pro-
cachectic cytokines, such as TNF-α or IL-1, exert their
activity through the nuclear factor-κB (NFκB) and the
p38 MAPK pathways. They promote structural muscle
protein breakdown and inhibit protein synthesis [10].
They also facilitate the ubiquitynation of sarcomeric
thick filaments, as well as other components of thick
filament [11].
Repressing inflammation could perhaps counteract
some of the manifestation of cancer cachexia. In this
regard, HMB possesses anti-inflammatory effect [6]. It
reduces TNFα and IFN-ɣ production by human
mononuclear cells in vitro [11] and also blocks some IL-
6- mediated pathways (Figure 1). Further, HMB
modifies activity of immune cells in human [11] and
nonhuman models [12]. Lymphocytes and macrophages,
in the presence of HMB in vitro, increase antibody
production and phagocytosis, respectively [12].
Decreased Regeneration
Cancer cachexia is accompanied by impaired
myogenic regeneration, thus contributing to muscle
wasting. Because skeletal muscle fibers are post-mitotic,
the regenerative process falls under the domain of
satellite cells [11]. In response to regenerative stimuli,
major signals including circulating or local factors (i.e.
mitogens), the paired box transcription factors (e.g.
Pax7), and the myogenic regulatory factors (e.g. MyoD,
myogenin) [13] direct satellite cells for regeneration [14].
In cachectic muscle, there is decreased regenerative
signal, such as myogenin, a protein associated with a
decreased aptitude of satellite cell progeny to
differentiate [15].
HMB stimulates the proliferation, differentiation,
and fusion of human myosatellite cells in vitro, thus
potentially increasing the regenerative capacity of
skeletal muscle. HMB also increases the protein
expression of myogenic regulatory factors (e.g., myoD
and myogenin) and gene transcription factors
(e.g., MEF2) [16-18]. Because the development and
progression of cancer cachexia is associated with
impaired regenerative capacity, these HMB-dependent
effects may favor muscle mass preservation.
Protein Turnover
IGF-I signaling promotes muscle growth and
prevents atrophy [19] through a cascade involving the
activation of protein kinase B (Akt) and mammalian
target of rapamycin (mTOR), among others [20]. During
cancer cachexia, decreased circulating and muscle
transcript levels of IGF-I have been noted, leading to
decreased rate of myofibrillar protein synthesis [21].
Journal of Nutritional Oncology, February 15, 2019, Volume 4, Number 1
Additionally, a tumor-secreted proteolysis-inducing
factor (PIF) induces generalized wasting [22]. PIF
provides the signal for protein degradation through
subsequent activation of nuclear factor kappa B (NF-B)
[23,24]. NF-kB appears to mediate protein degradation
through the ubiquitin-proteasome system [23]. Thus,
both NF-KB and FoxO can upregulate proteasome
activity in skeletal muscle, highlighting the importance
of these factors in driving cancer-induced muscle
atrophy.
Myostatin, a tumor-secreted protein belonging to
the transforming growth factor-β (TGF-β) family of
ligands, exerts inhibitory effects on muscle growth
through activity of the transcription factor Smad 2/3
[25,26]. Recently, myostatin signaling has been
implicated in the reduced protein synthesis observed
during cancer cachexia through inhibition of the
Akt/mTOR pathway [26]. Significantly elevated muscle
expression of myostatin mRNA and protein has been
noted in rodents with cachexia [27]. This implicates
myostatin as a promoter of muscle wasting by increasing
protein degradation and inhibiting protein synthesis, thus
altering overall host protein turnover.
Treatment with HMB attenuates protein
degradation and the expression of ubiquitin proteasome
subunits [28] (Figure 1). In vitro model of skeletal
muscle provided some indications that HMB attenuates
the depression of protein synthesis by PIF in myotubes
through multiple mechanisms [29]. HMB also stimulates
protein synthesis. While PIF suppresses protein
synthesis by 50%, HMB can attenuate this decrease to
~90% of control values [29], thus favoring protein
synthesis and muscle growth.
Therapy Induced Sarcopenia
Chemotherapy also contributes to cachexia, but its
effect on muscle wasting does not utilize the skeletal
muscle proteolytic system that is commonly implicated
in conditions characterized by muscle atrophy [30].
Instead, a combination of sarcoplasmic and mito-
chondrial alterations seem to be the main mechanisms
driving muscle wasting secondary to the use of
antineoplastic drugs [31,32]. It has been suggested that
chemotherapy administration to non-tumor bearing
animals causes mitochondrial depletion, release of ROS,
activation of ERK1/2 and p38 MAPKs-dependent
pathways as well as decreased AKT-dependent
anabolism [33-35]. Some of the same mechanisms are
also observed in the setting of cancer-promoted cachexia
[36] . These findings suggest that the concomitant use of
chemotherapy may exacerbate cancer-associated muscle
atrophy.
Evidence suggests that counteracting muscle
wasting can improve quality of life, reduce chemo-
therapy toxicity, thus allowing administration of higher
Journal of Nutritional Oncology, February 15, 2019, Volume 4, Number 1
and more effective doses of drug, and prolong survival
in the presence of tumors [37,38]. Supplementation with
HMB is effective in preventing inflammation- and
myostatin-associated muscle atrophy in tumor-bearing
mice, thus suggesting that supplementation should be
considered in association with chemotherapy [18]
(Figure 1).
Tumor Burden
Tumor growth occurs when cell proliferation
exceeds cell death and this imbalance can lead to
neoplastic processes. Cell death (e.g., apoptosis) is
controlled by several genes, especially those from the
Bcl-2 gene family. Bcl-2 is an anti-apoptotic gene, while
other proteins of this family (e.g., Bax) can exert pro-
apoptotic effects [39]. The Bax/Bcl-2 ratio is a key
factor in the regulation of apoptosis, since a high Bax/
Bcl-2 ratio can lead to apoptosis, whereas low ratio can
render cells resistant to apoptotic stimuli [40]. Milani et
al. reported that Walker-256 tumor cells constitutively
overexpress Bcl-2 protein, which renders this cell line
more resistant to programmed cell death [41].
The Bax/Bcl-2 ratio in Walker-256 tumors of
HMB-supplemented Wistar rats was 50% higher
compared to nonsupplemented rats [42]. In other animal
models, HMB supplementation reduces tumor growth,
mitigates tumor-induced cachexia and increases lifespan
Figure 1 Supplementation with HMB is effective in preventing inflammation- and myostatin-associated muscle atrophy in
tumor-bearing mice
·3 ·
[29,43,44].
HMB Biochemistry
HMB is a five-carbon organic acid synthesized in
the human body through the metabolism of the essential
amino acid leucine (LEU) via its metabolite α-
ketoisocaproate (α-KIC) [45]. In healthy individuals,
approximately 60% of dietary L-leucine is metabolized
after several hours, with roughly 5% (2–10% range) of
dietary L-leucine being converted to HMB [45]. The first
step in leucine metabolism is transamination to α-
ketoisocaproate (KIC) in muscle cells. KIC is excreted
from muscle and transported to the liver. In the liver
mitochondria, the majority of KIC is oxidized to
isovaleryl coenzyme A and ultimately metabolized to
acetoacetate and acetyl-CoA; approximately 5% of KIC
is metabolized to HMB by KIC-dioxygenase, a cytosolic
enzyme; HMB is then released into circulation. In a
multistep process, HMB is converted to β-hydroxy-β-
methylglutaryl-coenzyme A in the cytosol of muscle
cells which is then further converted to cholesterol.
Muscle produces its own cholesterol to maintain the
integrity of the cell membrane, as it cannot meet its
cholesterol needs via absorption from the circulation
[46]. Some of HMB’s reparative effects on damaged
tissues may be due to its metabolite HMG-CoA which
represents a carbon source for cholesterol synthesis thus
·4 ·
allowing for cell growth, function and regenerative
capability of the cell membrane. The effects of HMB on
muscle protein metabolism may also facilitate the
stabilization of muscle cell structure [43].
HMB and Cachexia
Although the effects of HMB on healthy subjects
do not necessarily apply to cancer cachexia patients,
they provide information that may be pertain. Supple-
mental HMB results in augmentation of muscle mass
and strength in healthy trained subjects [47]. An increase
is also observed in untrained individuals [48], but a
greatest effect is noted when HMB supplementation is
combined with an exercise program [49]. Prior training
status (trained versus untrained) or gender does not
appear to influence the effects of HMB on body
composition, strength and/or muscle damage [49].
The efficacy of HMB has been studied in several
conditions associated with cachexia, including trauma,
COPD, AIDS, cancer, and rheumatoid arthritis. The
results have been mixed. This discrepancy in response
calls for deeper analysis to understand possible variables
that may explain these differential responses. Different
pathophysiologic mechanisms underlie the cachexia/
sarcopenia of different disease states and this may
explain the differential response to HMB therapy.
For example, supplementation of rheumatoid
arthritis (RA) patients with HMB/ARG/GLN did not
reverse cachexia [50]. In RA patients, wasting is not
apparent as energy intake is normal; the decrease in
skeletal muscle mass is masked by an increase in fat
mass consequent to reduced physical activity and
resultant low levels of total energy expenditure [51]. RA
is a systemic disease characterized by cytokine-driven
alterations in protein and energy metabolism [52]
(Table1).
Table 1 Metabolic characteristics of cachexia in different
medical conditions
Post- Rheumatoid Cancer
bariatric Arthritis
Inflammatory Cytokines TNF ↑ TNF ↑ TNF ↑
IL1B ↓ IL1B ↑ IL1B ↑
IL6 ↓ IL6 ↑ IL6 ↑
Lipolysis/Adipogenesis ↑ - ↑
Fat free mass ↓ ↓ ↓ mentation increases survival time and promotes
Systemic inflammation ↓ ↑ ↑
Muscle wasting ↑ ↑ ↑
Total Energy ↓ ↓ ↑
Expenditure (TEE)
Fat mass ↓ ↑ ↓ Several studies have been carried out in this area,
Post bariatric surgery there is loss of fat and lean
body mass (LBM). This loss in muscle mass contributes
Journal of Nutritional Oncology, February 15, 2019, Volume 4, Number 1
to a reduction in resting metabolic rate (RMR). HMB/
ARG/GLN administration did not influence the decrease
in lean body mass, body mass index (BMI), fat free mass
(FFM) and resting metabolic rate (RMR) after
laparoscopic gastric bypass (LGB) [53,54]. Weight loss
following bariatric surgery is characterized by
extensive upregulation of TNF expression [55] (Table
1).
On the other hand, HMB supplementation in
trauma patients results in significant improvement in
nitrogen balance; the effect was not a result of lowered
muscle protein turnover [56]. Short-term supple-
mentation with HMB has anti-inflammatory and anti-
catabolic effect and improves pulmonary function in
COPD patients in an intensive care unit setting [57].
AIDS patients with cachexia also improved with HMB,
demonstrating increased muscle mass acquisition and
body weight [58]. HMB/ARG/GLN supplementation
also improved immune status, measured by increasing
CD3 and CD8 cells and decreasing the HIV viral load
[58]. It should be pointed out that AIDS-associated
wasting has many of the same metabolic characteristics
as cancer cachexia [59]. Both conditions are
characterized by increased mobilization of fat and
muscle, increased or normal metabolic rates, increased
rates of protein breakdown, and increased or normal
glucose turnover rates (Table 1) .
A possible explanation for divergent effects of
HMB may reside in the degree of catabolism present.
RA and bariatric patients gained less FFM than patients
with more severe cachectic conditions such as advanced
malignancy, trauma or HIV infection. As mentioned
before, HMB has more pronounced effects when used in
conjunction with physical training, suggesting that HMB
works better with higher resting energy.
HMB and Cancer Cachexia
Animal Models (Table 2)
HMB counteracts cancer cachexia by attenuating
muscle and body weight loss in Wistar rats inoculated
with AH-130 cells [60]. In this regard, HMB is more
potent than leucine, weight/weight [60,61]. In Walker
256 tumor-bearing rats, HMB counteracts cachexia and
also reduces tumor weight and tumor cell proliferation,
ex vivo [42,44]. In the same model, HMB supple-
metabolic changes in a time dependent manner, i.e., the
benefits are greater when there is sufficient time for
HMB to exert its effects [43].
HMB and Human Tumors
although definitive studies are lacking. In 32 cachectic
patients with advanced solid tumors (stage IV) of
diverse origin (colon, ovarian, lund, pancreatic, etc)
Journal of Nutritional Oncology, February 15, 2019, Volume 4, Number 1 ·5 ·

administration of a combination of HMB, arginine and
glutamine resulted in an average weight gain of 0.95 ±
0.66 kg in 4 weeks and a change in body composition
(FFM increase of 1.12 ± 0.68 kg). The FFM increase
was maintained over the 24 weeks and was accompanied
by an increase in lean body mass (LBM), improved
mood, less weakness, and improved hematological
parameters [62]. In another study, 472 patients with
advanced lung and other cancers were supplemented a
mixture of HMB, glutamine, and arginine or an
isonitrogenous, isocaloric control. The study showed a
strong trend towards higher FFM and BM in
HMB/ARG/GLN-supplemented patients; the effect-
iveness of HMB/ARG/GLN to reverse or prevent cancer
cachexia could not be evaluated as most of patients did
not complete the study [63] (Table 3).
As a part of the multi-model therapeutic approach a
tailored exercise program can be added in addition to
HMB in cancer patients.
Dosage and Safety
Previous studies investigating the effect of HMB
administration have shown that supplementation using
doses of 320 mg/kg of body weight per day increases the
lifespan in Walker 256 tumor-bearing rats [43].
However, that dose is approximately 4 times what is
typically administered to humans. Later, it was
demonstrated that 125 mg/kg/day (equivalent to 1.3
g/day human dose of HMB) in MAC 16 tumor-bearing
mice was enough to achieve significant reduction of
tumor growth and attenuation of cancer cachexia
symptoms [64].

Table 2 Effect of HMB in animal tumor models

Reference Model Intervention Dosage Significant Findings
[56] MAC16 cancer- HMB 125 mg/kg - attenuated the onset of weight loss, accompanied
induced weight loss by a small reduction in tumor growth rate.
[61] Walker 256 tumors in HMB 320 mg/kg - increased survival time and promoted metabolic
rats changes in cancer-bearing animals.
-effect is dependent on length of time of therapy.
[77] Walker 256 HMB 76 mg/kg - decreased tumor weight
tumors in rats - tumor cell proliferation ex vivo
[56] Walker 256 tumors HMB treatment 76 mg/kg -decreased tumor burden.
in Wistar rats pre-tumor inoculation
[57] AH-130 tumor cells in HMB treatment 4% HMB - positive effect on cancer-related wasting.
Wistar rats pre-tumor inoculation -enriched chow
[55] murine HMB vs Leucine 250mg/Kg HMB - more potent than leucine in counteracting cancer
adenocarcinoma 16 cachexia
tumor

Table 3 Summary of use of HMB in human diseases with cachexia

Reference Condition # Dosage Duration Changes in body
Subjects (in weeks) composition
BM FFM FM
[73] Cancer 32 3 g HMB/14 g ARG/14g GLN 24 + + =
[74] Cancer 446 3 g HMB/14 g ARG/14 g GLN 8 + + NA
[75] Trauma 72 3g HMB vs 3 g HMB/14 g ARG/14 g GLN 4 NA NA NA
[76] COPD 34 3g HMB 1 = NA NA
[69] RYGB 30 2.4 g HMB/14 g ARG/14 g GLN/ 2 g 8 = = =
sugar/15.6 g carbohydrates
[70] LGB 30 2.4 g HMB/14 g ARG/14 g GLN/ 4 g 8 = = =
sugar/15.6 g carbohydrates
[67] RA 40 3g HMB vs 3 g HMB/14 g ARG/14 g GLN 12 = = =
[66] AID 68 3g HMB vs 3 g HMB/14 g ARG/14 g GLN 8 + + =
[63] Healthy subjects/ 34 / 43 / 3g HMB vs 3 g HMB/14 g ARG/14 g GLN 4-24 NA NA NA
HIV/Cancer 32
HMB, β-Hydroxy β-Methylbutyrate; ARG, Arginine; GLN, Glutamine; COPD, Chronic Obstructive Pulmonary Disease; RYGB,
Roux-en-Y gastric bypass; LGB, Laparoscopic Roux-en-Y Gastric Bypass; AID, Acquired Immune Deficiency Syndrome; BM, Body
Mass; FFM, Fat-free body mass; RA, Rheumatoid arthritis
·6 ·
The dose used in various HMB studies range from
38-76mg/kg/day in human beings, all of the studies that
supplementary HMB to diseased subjects (Trauma,
COPD, AIDs, Cancer, Rheumatoid arthritis) used a dose
of 2.4-3g/day of HMB. Gallagher PM et al. showed that
in healthy untrained subjects supplementation of 6g/day
of HMB produced a greater increase in peak isokinetic
torque than 3g of HMB without compromising liver
function, renal function, immune system or lipid profile
during resistance training [48]. Whether dosage higher
than 3g/day of HMB can attain superior results in cancer
patients has to be yet investigated. In his study,
Gallagher PM et al have shown that an 8-week HMB
supplementation at different dosages have no adverse
effects on hepatic enzyme function, lipid profile, renal
function or on the immune system in untrained men
undergoing resistance training [48]. Higher dosages
seem promising given the safety profile of HMB.
Subjects receiving HMB as a free acid gel
presented quicker and greater plasma concentrations and
improved clearance of plasma HMB versus those
receiving calcium HMB (CaHMB) gelatine capsules.
This new gel formulation could improve HMB
availability and efficacy to tissue [65]. Many of the more
recent studies use a combination supplementation of
HMB/Arg/GLN as this preparation is readily available
commercially. The combination has been shown to be
synergistic in several conditions such as wound healing
and gain in muscle mass.
Conclusion
HMB counteracts cachexia through altering many
metabolic pathways. HMB promotes myogenic events,
suppresses proteasome activity, and activates protein
synthesis and skeletal muscle growth. HMB also
represses inflammation, reduces tumor growth, and
mitigates tumor-induced cachexia and increases lifespan.
However, HMB is not effective in counteracting all
types of cachexia. The pharmacological properties of
HMB might become apparent only in highly catabolic
cachexic patients. HMB supplementation contributed to
preserve FFM in hypermetabolic cachexia such as
cancer, AIDS, and following trauma, but it did not have
any effect in hypometabolic cachexia such as RA
cachexia, and post bariatric surgeries.
These benefits in cancer cachexia were observed at
a dosage of 3g/day. Higher dosages (6g/day) were found
to have greater increase in peak isokinetic torque, in
healthy individuals, without compromising liver
function, renal function, immune system or lipid profile
during resistance training. Further studies are necessary
to confirm the effect of higher dosages of HMB in
cancer cachexia, given its safety profile.
HMB supplementation works in a time dependent
manner; results are greater when there is sufficient time
Journal of Nutritional Oncology, February 15, 2019, Volume 4, Number 1
for HMB to exert its effects [43]. Add to that, a greater
increase in muscle mass and strength was seen when
HMB supplementation was combined with an exercise
program [48] as compared to HMB supplementation
alone.
In addition to a tailored exercise program in high
risk cancer patients, future trials should investigate the
effectiveness of initiating HMB supplementation (alone
or in combination with other substrates) as a part of the
multi-model prophylactic/therapeutic approach even
before cachexia ensues.
Conflict of interest
The authors declare that they have no competing
interests.
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Accepted: February 1, 2019