Alcohol‐Mediated Dysregulation of Histone Deacetylases Decreases Myoblast Differentiation in SIV‐Infected Male Rhesus Macaques
Authors: Adler Katherine , Molina Patricia , Simon Liz 
Published: June 2021

BackgroundLoss 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. Skeletal muscle mass maintenance, repair and regeneration are mediated by proliferation and differentiation of satellite cells (myoblasts). Previously we demonstrated that chronic alcohol decreases satellite cell myogenic gene expression and differentiation. The aim of this study was to determine whether alcohol‐mediated epigenetic dysregulation, specifically an increase in Class IIA histone deacetylases (HDACs), mechanistically contributes to the decreased differentiation potential of satellite cells.MethodsSkeletal muscle tissue was excised from simian immunodeficiency virus (SIV) infected‐ and chronic binge alcohol (CBA)‐administered rhesus macaques with and without antiretroviral therapy (ART) treatment (VEH/SIV/ART−, VEH/SIV/ART+, CBA/SIV/ART−, CBA/SIV/ART+). Class IIA HDAC expression and activity was determined in skeletal muscle. The effect of ethanol (ETOH; 50 mM) and Class IIA HDAC (selective inhibitor TMP195) on differentiation was determined in myoblasts isolated from skeletal muscle of six naïve male rhesus macaques, yielding four treatment groups (VEH/VEH, VEH/TMP195, ETOH/VEH, ETOH/TMP195). qPCR was performed on myoblasts after proliferation (Day 0) and after 3 and 5 days of differentiation (Day 3 and Day 5, respectively). Proliferation was quantified at Day 0 using KI67 immunohistochemistry. Differentiation into myotubes was quantified using Jenner‐Giemsa staining. Data were analyzed using 2 way‐ANOVA and t‐test.ResultsCBA increased HDAC4 and HDAC11 gene expression in skeletal muscle and myoblasts of SIV‐infected macaques. CBA and ART increased HDAC activity in skeletal muscle and this was positively correlated with HDAC4 gene expression. CBA and SIV infection significantly decreased myogenic differentiation and expression of genes implicated in myogenesis. In vitro ETOH significantly decreased expression of myogenic genes, myogenic factor 5 and myocyte‐specific enhancer factor 2C, and Class IIA HDAC expression during proliferation. ETOH significantly increased Class IIA HDAC expression at Day 5 of differentiation and this was negatively correlated with fusion index and myotube formation.ConclusionsOur results suggest that alcohol‐mediated increases in HDAC expression mechanistically contributes to decreased myoblast differentiation. Results will indicate whether inhibition of Class IIA HDAC restores myogenic potential of alcohol‐treated myoblasts and expression of specific myogenic genes that are dysregulated by alcohol‐mediated histone deacetylation. Data will inform whether HDACs are therapeutic targets for improving or restoring skeletal muscle metabolic mass in PLWH with alcohol use disorder.Support or Funding InformationK01AA024494 and AA09803 from the NIAAA/NIHThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.