β-Hydroxy-β-methylbutyrate reduces myonuclear apoptosis during recovery from hind limb suspension-induced muscle fiber atrophy in aged rats

Abstract

β-Hydroxy-β-methylbutyrate (HMB) is a leucine metabolite shown to reduce protein catabolism in disease states and promote skeletal muscle hypertrophy in response to loading exercise. In this study, we evaluated the efficacy of HMB to reduce muscle wasting and promote muscle recovery following disuse in aged animals. Fisher 344×Brown Norway rats, 34 mo of age, were randomly assigned to receive either Ca-HMB (340 mg/kg body wt) or the water vehicle by gavage (n = 32/group). The animals received either 14 days of hindlimb suspension (HS, n = 8/diet group) or 14 days of unloading followed by 14 days of reloading (R; n = 8/diet group). Nonsuspended control animals were compared with suspended animals after 14 days of HS (n = 8) or after R (n = 8). HMB treatment prevented the decline in maximal in vivo isometric force output after 2 wk of recovery from hindlimb unloading. The HMB-treated animals had significantly greater plantaris and soleus fiber cross-sectional area compared with the vehicle-treated animals. HMB decreased the amount of TUNEL-positive nuclei in reloaded plantaris muscles (5.1% vs. 1.6%, P < 0.05) and soleus muscles (3.9% vs. 1.8%, P < 0.05). Although HMB did not significantly alter Bcl-2 protein abundance compared with vehicle treatment, HMB decreased Bax protein abundance following R, by 40% and 14% (P < 0.05) in plantaris and soleus muscles, respectively. Cleaved caspase-3 was reduced by 12% and 9% (P < 0.05) in HMB-treated reloaded plantaris and soleus muscles, compared with vehicle-treated animals. HMB reduced cleaved caspase-9 by 14% and 30% (P < 0.05) in reloaded plantaris and soleus muscles, respectively, compared with vehicle-treated animals. Although, HMB was unable to prevent unloading-induced atrophy, it attenuated the decrease in fiber area in fast and slow muscles after HS and R. HMB's ability to protect against muscle loss may be due in part to putative inhibition of myonuclear apoptosis via regulation of mitochondrial-associated caspase signaling.

Effect of beta-hydroxy-beta-methylbutyrate supplementation on muscle loss in older adults: A systematic review and meta-analysis

“…Animal studies have shown that supplemental HMB may enhance protein synthesis in neonatal skeletal muscle by stimulating translation initiation (Wheatley et al, 2014), which may improve survival rates of low-birth-weight infants. In addition, HMB supplementation suppresses apoptotic signaling and the apoptotic index during muscle disuse and during reloading periods after disuse in aged rats (Hao et al, 2011) and improves proliferation of satellite cells in muscles from aged rats in response to a loading stimulus following a period of disuse (Alway, Pereira, Edens, Hao, & Bennett, 2013). Population surveys suggest that HMB can be used to enhance recovery by attenuating exercise induced skeletal muscle damage in trained (Wilson et al, 2013b) and untrained populations (Wilson et al, 2009).…”

REDD2 expression in rat skeletal muscle correlates with nutrient-induced activation of mTORC1: responses to aging, immobilization, and remobilization

“…The molecular basis for the delayed recovery of muscle mass with remobilization is unknown. One potential mechanism could be linked to myonuclear apoptosis that occurs during immobilization and is still prevalent during reloading (27,51). It is also tempting to speculate that it may be related to a reduction in RNA content, and thus ribosome abundance.…”

Regulation of Satellite Cell Function in Sarcopenia

“…We have previously shown that HMB could improve muscle recovery in old rats with sarcopenia that had been subjected to unloading, in part via an increase in satellite cell proliferation and a reduction of nuclear apoptosis (Hao et al, 2011). HMB also has been shown to have direct effects on proliferation of myoblasts in vitro (Kornasio et al, 2009), although, its efficacy on satellite cell activation has not previously been evaluated in vivo in aged immobilized animals.…”