Chronic binge alcohol (CBA) decreases miR‐206 expression in the skeletal muscle of Simian Immunodeficiency Virus (SIV)‐infected macaques

Abstract

Studies using a non-human primate model of SIV infection have demonstrated that myoblasts isolated from CBA/SIV macaques have altered myogenic gene expression and decreased myoblast differentiation potential, suggesting impaired skeletal muscle (SKM) regeneration as a mechanism contributing to loss of SKM at end stage SIV. We hypothesized that the altered SKM milieu in CBA/SIV macaques dysregulates SKM specific microRNAs that regulate gene transcription necessary for myogenesis. Histone deacetylase 4 (HDAC4) negatively regulates myogenesis by associating with myocyte enhancer factor 2 (MEF2) and is a target of miR-206. CBA or isocaloric sucrose (SUC) were administered daily via a gastric catheter to male rhesus macaques beginning 3 mo. prior to SIV infection and continued throughout the duration of study. At ten weeks post-SIV infection, daily administration of antiretroviral therapy (ART; tenofovir and emtricitabine) was initiated in a subset of both SUC/SIV and CBA/SIV groups and continued for the duration of the study. SKM was obtained at necropsy (~11 mo. post-SIV) from SUC/SIV/ART± and CBA/SIV/ART± macaques. SKM of CBA/SIV macaques showed significantly decreased expression of miR-206 and MEF2C mRNA compared to SKM of SUC/SIV irrespective of ART. In contrast, SKM of CBA/SIV macaques showed increased mRNA expression of HDAC4 compared to SUC/SIV irrespective of ART. These results suggest that decreased miR-206 in CBA/SIV macaques favors upregulation of HDAC4, which represses MEF2C potentially contributing to impaired myogenesis. Future studies will verify the functional implications of the altered myomiR profile in myoblasts and its contribution to impaired SKM regeneration in CBA/SIV macaques.