Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation

Cell Rep. 2016 Sep 13;16(11):2802-2810. doi: 10.1016/j.celrep.2016.08.005.


Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity.

Keywords: HDAC4; HDAC5; MEF2; Skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalytic Domain
  • Cell Line
  • Co-Repressor Proteins / metabolism*
  • Energy Metabolism* / drug effects
  • Energy Metabolism* / genetics
  • Gene Expression Regulation / drug effects
  • Histone Deacetylases / metabolism*
  • Hydroxylamines / administration & dosage
  • Hydroxylamines / pharmacology
  • Lipid Metabolism* / drug effects
  • Lipid Metabolism* / genetics
  • MEF2 Transcription Factors / genetics
  • MEF2 Transcription Factors / metabolism
  • Mice
  • Mutation / genetics
  • Oxidation-Reduction
  • Physical Conditioning, Animal
  • Protein Binding / drug effects
  • Quinolines / administration & dosage
  • Quinolines / pharmacology
  • Transcription, Genetic / drug effects


  • Co-Repressor Proteins
  • Hydroxylamines
  • MEF2 Transcription Factors
  • Quinolines
  • scriptaid
  • Hdac5 protein, mouse
  • Histone Deacetylases