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

Vidhi Gaur, Timothy Connor, Andrew Sanigorski, Sheree D. Martin, Clinton R. Bruce, Darren C. Henstridge, Simon T. Bond, Kevin A. McEwen, Lyndal Kerr-Bayles, Trent D. Ashton, Cassandra Fleming, Min Wu, Lisa S. Pike Winer, Denise Chen, Gregg M. Hudson, John W R Schwabe, Keith Baar, Mark A. Febbraio, Paul Gregorevic, Frederick M. PfefferKen R. Walder, Mark Hargreaves, Sean L. McGee

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2802-2810
Number of pages9
JournalCell Reports
Volume16
Issue number11
DOIs
StatePublished - Sep 13 2016

Keywords

  • HDAC4
  • HDAC5
  • MEF2
  • Skeletal muscle

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Gaur, V., Connor, T., Sanigorski, A., Martin, S. D., Bruce, C. R., Henstridge, D. C., Bond, S. T., McEwen, K. A., Kerr-Bayles, L., Ashton, T. D., Fleming, C., Wu, M., Pike Winer, L. S., Chen, D., Hudson, G. M., Schwabe, J. W. R., Baar, K., Febbraio, M. A., Gregorevic, P., ... McGee, S. L. (2016). Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation. Cell Reports, 16(11), 2802-2810. https://doi.org/10.1016/j.celrep.2016.08.005