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

Physiol Genomics. 2019 Sep 1;51(9):471-479. doi: 10.1152/physiolgenomics.00043.2019. Epub 2019 Aug 9.


Loss of functional metabolic muscle mass remains a strong and consistent predictor of mortality among people living with human immunodeficiency virus (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 maintenance and repair 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 antiretroviral therapy increased HDAC activity in SKM and this was positively correlated with HDAC4 gene expression. In vitro ethanol (ETOH) treatment increased HDAC expression during differentiation and decreased differentiation potential of myoblasts. HDAC expression was negatively correlated with fusion index and myotube formation, indicators of differentiation potential. Treatment with a Class II HDAC inhibitor, TMP195, restored differentiation in ETOH-treated myoblasts. MEF2C expression at day 3 of differentiation 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.

Keywords: chronic alcohol; histone deacetylases; stem cell differentiation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Retroviral Agents / therapeutic use
  • Benzamides / pharmacology
  • Cell Differentiation / drug effects*
  • Epigenesis, Genetic / drug effects*
  • Ethanol / administration & dosage
  • Ethanol / pharmacology*
  • Gene Expression Regulation / drug effects
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / genetics*
  • MEF2 Transcription Factors / metabolism
  • Macaca mulatta
  • Male
  • Muscle Development / drug effects
  • Muscle Development / genetics
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Oxadiazoles / pharmacology
  • Satellite Cells, Skeletal Muscle / metabolism*
  • Satellite Cells, Skeletal Muscle / virology
  • Signal Transduction / drug effects
  • Simian Acquired Immunodeficiency Syndrome / drug therapy
  • Simian Acquired Immunodeficiency Syndrome / enzymology*
  • Simian Acquired Immunodeficiency Syndrome / virology
  • Simian Immunodeficiency Virus*
  • Sucrose / administration & dosage
  • Sucrose / pharmacology


  • Anti-Retroviral Agents
  • Benzamides
  • Histone Deacetylase Inhibitors
  • MEF2 Transcription Factors
  • Oxadiazoles
  • TMP195
  • Ethanol
  • Sucrose
  • Histone Deacetylases