Alcohol accentuates simian immunodeficiency virus‐induced alterations in the skeletal muscle milieu contributing to impaired satellite cell myogenic differentiation (732.5)

Abstract

Muscle wasting adversely affects survival in people living with HIV/AIDS (PLWHA). Studies using a non‐human primate model of SIV infection have demonstrated that chronic binge alcohol (CBA) consumption accentuates muscle wasting in AIDS. Alcohol‐accentuation of muscle wasting appears to be due to increased protein degradation and inability to rebuild muscle mass, which we predict is due to an inability of satellite cells (SCs), the precursors of skeletal muscle fibers, to form new myofibers. We have previously demonstrated that CBA impairs the ex vivo myogenic differentiation of SCs, the muscle progenitor cells. Moreover, there was a significant increase in Smad2 gene expression, the downstream intermediate of transforming growth factor‐ß1 (TGF‐B1) signaling, in CBA SCs suggesting a role of this pathway in inhibiting myogenesis. Based on our preliminary studies and the suggestion that TGF‐ß1 may negatively regulate SC activation, we hypothesized that the chronic inflammatory and oxidative skeletal muscle milieu leads to a profibrotic phenotype of SCs due to activation of TGF‐β1 inhibiting their myogenic differentiation. Using muscle tissue or SCs isolated from CBA or sucrose fed SIV‐infected rhesus macaques, we demonstrate that there is a significant increase in the expression of TGF‐β1 expression in the muscle and decreased myogenic differentiation of SCs of the CBA‐SIV animals. There was also increased expression of Smad2 in the CBA‐SIV SCs. The results provide evidence of dysregulation of the skeletal muscle milieu due to chronic alcohol in SIV infection that impairs SC myogenic differentiation.Grant Funding Source: NIH P60AA09803