Epigenomic mechanisms of alcohol-induced impaired differentiation of skeletal muscle stem cells; role of Class IIA histone deacetylases.

Abstract

Loss of functional metabolic muscle mass remains a strong and consistent predictor of mortality among people living with HIV (PLWH). PLWH have a higher incidence of alcohol use disorder (AUD), and myopathy is a significant clinical comorbidity due to AUD. One mechanism of skeletal muscle (SKM) mass repair and maintenance is by differentiation and fusion of satellite cells (SCs) to existing myofibers. Previous studies demonstrated that chronic binge alcohol (CBA) administration decreases SC differentiation potential, myogenic gene expression, and miR-206 expression in simian immunodeficiency virus (SIV) - infected male rhesus macaques and that miR-206 targets the Class IIA histone deacetylase, HDAC4. The aim of this study was to determine whether alcohol-induced increases in Class IIA HDACs mediate the observed decrease in differentiation potential of SCs. Data show that CBA dysregulated HDAC gene expression in SKM and myoblasts of SIV-infected macaques. CBA and ART increased HDAC activity in SKM and this was positively correlated with HDAC4 gene expression. In vitro ETOH decreased myogenic gene expression during proliferation, increased HDAC expression during differentiation, and decreased differentiation potential of myoblasts. HDAC expression during differentiation was negatively correlated with fusion index and myotube formation, indicators of differentiation potential. Treatment with a Class II HDAC selective inhibitor, TMP195, partially restored differentiation in ETOH-treated myoblasts and increased MEF2C expression. MEF2C expression was positively correlated with fusion index and myotube formation. These findings suggest that an alcohol-mediated increase in Class IIA HDAC expression contributes to decreased myoblast differentiation by downregulating MEF2C, a transcription factor critical for myogenesis.