Acute muscle wasting occurs early and rapidly during the first week of critical illness and
contributes substantially to weakness acquired in the ICU. Muscle wasting and subsequent
weakness is associated with delayed liberation from mechanical ventilation, prolonged
hospital length of stay (LOS), long-term functional disability, and worse quality of life.
Moreover, low muscle volume and ICU-acquired weakness increases the risk of mortality in
critically ill patients. Although several factors likely accelerate skeletal muscle wasting
during critical illness (e.g., immobility, muscle unloading, inflammation, multi-organ
failure), the understanding of the underlying mechanisms remains limited and is reflected in
the lack of effective interventions to prevent the loss of muscle mass in ICU patients.
Muscle mass is maintained through balanced protein breakdown and synthesis . As such, for
wasting to occur, catabolic pathways must be increased relative to anabolic processes. In
general, nutritional status is an important factor for maintaining skeletal muscle
homeostasis. However, adequate caloric delivery is often challenging in ICU patients and
recent data suggest that high protein delivery in early critical illness may adversely impact
muscle protein synthesis. Moreover, randomized, placebo-controlled, clinical trials (RCTs) in
ICU patients do not support the use of aggressive early macronutrient delivery. Such findings
emphasize the need for targeted therapies to enhance anabolic pathways, which may improve
clinical outcomes in critically ill patients.
The amino acid leucine is widely regarded for its anabolic effects on muscle metabolism, but
the concentrations required to maximize its anti-proteolytic effects are far greater than the
concentrations required to maximally stimulate protein synthesis. This has resulted in the
search for leucine metabolites that may also be potent mediators of anabolic processes in
skeletal muscle -- one such compound is β-hydroxy-β-methylbutyrate (HMB).
HMB is thought to primarily facilitate protein synthesis through stimulation of mammalian
target of rapamycin (mTOR), a protein kinase responsive to mechanical, hormonal, and
nutritional stimuli that plays a central role in the control of cell growth. Indeed,
preclinical studies demonstrate that HMB supplementation increases phosphorylation of mTOR as
well as its downstream targets. Preclinical data also suggest that HMB supplementation
results in an increase in skeletal muscle insulin-like growth factor 1(IGF-1) levels, which
may further stimulate mTOR. In addition, HMB may influence systemic levels of myostatin, a
key negative regulator of mature skeletal muscle growth. Myostatin has been shown to reduce
muscle protein synthesis by inhibiting mTOR signaling and by increasing proteolytic
mechanisms. Recent preclinical data suggest that HMB may reduce myostatin levels and
attenuate skeletal muscle atrophy. Furthermore, preclinical data has shown that HMB also
stimulates the release of irisin, a newly discovered myokine, which up-regulates IGF-1 and
inhibits myostatin.
On the other hand, skeletal muscle proteolysis is thought to occur primarily through the
ubiquitin-proteasome system, which is an energy-dependent proteolytic system that degrades
intracellular proteins. The activity of this pathway is thought to be regulated through
expression of nuclear factor kappa B (NF-κB), which is significantly increased in conditions
such as fasting, immobilization, bed rest, and in various disease states. In preclinical
studies, HMB has been shown to decrease proteasome expression and reduce activity of this
pathway during catabolic states. Furthermore, caspase proteases (in particular, caspase
protease-3 and caspase protease-9) are thought to induce skeletal muscle proteolysis through
apoptosis of myonuclei. Preclinical data suggest that in catabolic states, HMB attenuates the
up-regulation of caspases, which in turn, reduces myonuclear apoptosis and reduces skeletal
muscle protein degradation.
Randomized controlled trials (RCTs) that have assessed the effect of HMB supplementation on
clinical outcomes in patients with chronic diseases are limited, and even fewer studies have
assessed its effects on skeletal muscle metabolism during critical illness. Furthermore,
despite compelling preclinical evidence, the exact mechanisms underlying the effect of HMB
supplementation during acute catabolic stress in humans is not well defined.
Therefore, the investigators goal is to study the impact of early HMB supplementation on
skeletal muscle mass in surgical ICU patients and to explore the mechanisms by which HMB may
exert beneficial effects on skeletal muscle metabolism during the course of critical illness.