Literature Review

Preserving Muscle Mass with Beta-Hydroxy-Beta Methylbutyrate

Muscle, the vital and venerated instrument of athletic performance, is a dynamic tissue in which proteins are continually synthesized and degraded. Thus, effective strategies in sports nutrition must address an equilibrium between protein synthesis and protein degradation. The branched chain amino acids (BCAA) are exemplary agents that shift this equation in favor of protein synthesis. Of the BCAA, the most physiologically important is leucine.

In addition to its structural role as a building block of proteins, leucine plays a functional role as a stimulus of the ribosome, the cellular organelle that translates the genetic code into new muscle protein [1]. However, in clinical studies, leucine supplementation stimulates protein synthesis only transiently, lasting several hours. Conversely, clinical studies of the leucine metabolite, β-hydroxy β-methylbutyrate (HMB), demonstrate a sustainable increase in protein synthesis and accrual of muscle protein over time [2-4].

Shifting the equation

HMB stimulates protein synthesis through activating growth factors and signal transduction pathways [5]. Many of these pathways normally require glucose and insulin to properly engage. However, HMB enlists them in the absence of glycemic stimuli, suggesting that HMB may support protein synthesis during periods of restricted carbohydrate intake [1]. HMB also stimulates genomic factors that support muscle cell proliferation and development [5].  While these actions collectively promote protein accretion, the most powerful action of HMB is inhibition of protein degradation, or catabolism. In this capacity, HMB may preserve existing muscle mass during periods of intense or prolonged training.

To date, HMB has been the subject of over 30 human clinical studies. Muscle mass and strength gains have been documented across a wide range of age groups and activity levels [2-4,6].  In a study of young men and women engaged in moderate-exercise programs, HMB produced a 27% increase in strength compared to placebo over a 4-week period [3]. Reported changes in lean mass with HMB supplementation, in combination with resistance exercise, have reached 200% [6].  The most dramatic results have been evident during periods of high intensity or prolonged training, in which protein catabolism is typically accelerated.

Attenuation of protein catabolism can preserve muscle strength in endurance athletes engaged in strenuous, high-volume training. Studies of HMB in endurance athletes have revealed additional performance benefits that extend beyond the protein equation. For example, a study of trained cyclists revealed improvements in VO2 max after only 2 weeks of HMB supplementation [7]. In a subsequent placebo-controlled trial of trained runners, HMB reduced plasma markers of muscle damage associated with daily long-distance running [8]. This effect likely explains reductions in muscle soreness reported in a previous study [9].  Thus, in addition to promoting lean mass accretion, HMB supports critical determinants of endurance performance. Taken together, these studies substantiate the multimodal efficacy of HMB in promoting muscle gains and attenuating muscle damage in response to exercise.

Muscle longevity

After the age of 50, both men and women lose approximately 1-2% of their total muscle mass per year [10]. Age-related muscle loss is partially ascribed to elevated activity of the proteasome, a cellular organelle that degrades protein. In our youth, the proteasome is conservative, degrading only proteins that the body does not need. As we age, however, the proteasome becomes indecisive, degrading both essential and nonessential proteins. This loss of selectivity is partially mediated by inflammatory cytokines and free radicals in aging cells. HMB antagonizes these mediators to mitigate proteasome activity [11].

The proteasome is a cellular organelle that degrades protein. In young organisms, the proteasome prefers to degrade proteins that the body does not need. With aging, it tends to degrade more essential muscle proteins. Conditions involving inflammation activate proteasome activity, while dietary agents like leucine and its metabolite, HMB, reduce proteasome activity. (Image obtained from RCSB Protein Data Bank)

The anticatabolic actions of HMB have produced remarkable clinical outcomes in studies of older individuals. Gains in lean body mass with HMB supplementation have been evident in both active and sedentary subjects [4,6]. In a 4-week clinical trial of 39 bedridden elderly nursing home residents, increased nitrogen retention, an indicator of lean body mass accretion, was evident after only 14 days of HMB supplementation [6].  In a double-blind, placebo-controlled study of men and women averaging 70 years of age, HMB supplementation, combined with daily exercise, promoted accretion of fat-free mass with concurrent reduction in body fat. These changes in body composition were similar to those previously observed in younger subjects [4].

Strategic combinations

A combination of HMB and creatine was investigated in a double-blind, placebo-controlled study of 40 subjects engaged in a 3-week program of resistance exercise. The effects of the combination on weight lifting performance and lean body mass were additive [12].  Several molecular targets of creatine and HMB intersect with pathways engaged by the antioxidant alpha lipoic acid, suggesting potential synergy [13].  In muscle, alpha lipoic acid reduces oxidative stress, improves insulin sensitivity and may increase creatine assimilation [14].  


HMB exhibits an esoteric, yet thoroughly evaluated combination of anabolic and anticatabolic mechanisms that no dietary agent can recapitulate. Improvements in strength and lean body mass are not only relevant to the performance of athletes, but to the health and physical function of the aging population. Clinical research on HMB and lean body mass suggests that young and elderly subjects of diverse clinical and athletic backgrounds may benefit from daily supplementation.


  1. Aversa Z, Bonetto A, Costelli P, Minero VG, Penna F, Baccino FM, Lucia S, Rossi Fanelli F, Muscaritoli M. β-hydroxy-β-methylbutyrate (HMB) attenuates muscle and body weightloss in experimental cancer cachexia. Int J Oncol. 2011, 38:713-720.
  2. Nissen S, Sharp R, Ray M, Rathmacher JA, Rice D, Fuller JC Jr, Connelly AS, Abumrad N. Effect of leucine metabolite beta-hydroxy-beta-methylbutyrate on muscle metabolismduring resistance-exercise training. J Appl Physiol. 1996, 81:2095-2104.
  3. Panton LB, Rathmacher JA, Baier S, Nissen S. Nutritional supplementation of the leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) during resistance training.Nutrition. 2000, 16:734-739.
  4. Vukovich MD, Stubbs NB, Bohlken RM. Body composition in 70-year-old adults responds to dietary beta-hydroxy-beta-methylbutyrate similarly to that of young adults. J Nutr.2001, 131:2049-2052.
  5. Kornasioa R, Riedererb I, Butler-Browneb G, Moulyb V, Unia Z and Halevya O. β-hydroxy-β-methylbutyrate (HMB) stimulates myogenic cell proliferation, differentiation andsurvival via the MAPK/ERK and PI3K/Akt pathways. Biochim Biophys Acta. 2009,1793:755-763.
  6. Hsieh LC, Chow CJ, Chang WC, Liu TH, Chang CK. Effect of beta-hydroxy-beta-methylbutyrate on protein metabolism in bed-ridden elderly receiving tube feeding. Asia Pac JClin Nutr. 2010, 19:200-208.
  7. Vukovich, MD, Adams GD. Effect of HMB on VO2 peak and maximal lactate in endurance-trained cyclists. Med Sci Sports Exerc. 1997, 29:1432.
  8. Knitter AE, Panton L, Rathmacher JA, Petersen A, Sharp R. Effects of beta-hydroxy-beta-methylbutyrate on muscle damage after a prolonged run. J Appl Physiol. 2000,89:1340-1344.
  9. Byrd PL, Mehta PM, DeVita P, Dyck D, Hickner RC. Changes in muscle soreness and strength following downhill running: Effects of creatine, HMB, and betagen supplementation.Med Sci Sports Exerc. 1999, 31:S263.
  10. Hughes VA, Frontera WR, Wood M, Evans WJ, Dallal GE, Roubenoff R, Fiatarone Singh MA. Longitudinal muscle strength changes in older adults: influence of muscle mass,physical activity, and health. J Gerontol A Biol Sci Med Sci. 2001, 56:B209-B217.
  11. Eley HL, Russell ST, Tisdale MJ. Mechanism of attenuation of muscle protein degradation induced by tumor necrosis factor-α and angiotensin II by β-hydroxy-β-methylbutyrate.Am J Physiol Endocrinol Metab. 2008, 295:E1417-E1426.
  12. Jówko E, Ostaszewski P, Jank M, Sacharuk J, Zieniewicz A, Wilczak J, Nissen S. Creatine and beta-hydroxy-beta-methylbutyrate (HMB) additively increase lean body mass andmuscle strength during a weight-training program. Nutrition. 2001, 17:558-566.
  13. Saengsirisuwan V, Perez FR, Sloniger JA, Maier T, Henriksen EJ. Interactions of exercise training and alpha-lipoic acid on insulin signaling in skeletal muscle of obese Zucker rats.Am J Physiol Endocrinol Metab. 2004, 287:E529-E536.
  14. Burke DG, Chilibeck PD, Parise G, Tarnopolsky MA, Candow DG. Effect of alpha-lipoic acid combined with creatine monohydrate on human skeletal muscle creatine andphosphagen concentration. Int J Sport Nutr Exerc Metab. 2003 Sep;13(3):294-302.

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