1. Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation
- Author
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Mark A. Febbraio, Kevin A. McEwen, Sheree D. Martin, John W.R. Schwabe, Lisa S. Pike Winer, Darren C. Henstridge, Andrew Sanigorski, Clinton R. Bruce, Vidhi Gaur, Sean L. McGee, Simon T. Bond, Frederick M. Pfeffer, Cassandra L. Fleming, Min Wu, Paul Gregorevic, Trent D. Ashton, Mark Hargreaves, Denise Chen, Timothy Connor, Keith Baar, Ken Walder, Lyndal Kerr-Bayles, and Gregg M. Hudson
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Transcription, Genetic ,Skeletal muscle ,Biology ,Hydroxylamines ,General Biochemistry, Genetics and Molecular Biology ,Histone Deacetylases ,Cell Line ,03 medical and health sciences ,Mice ,Lipid oxidation ,Internal medicine ,Catalytic Domain ,Physical Conditioning, Animal ,medicine ,Animals ,lcsh:QH301-705.5 ,Regulation of gene expression ,Histone deacetylase 5 ,Histone deacetylase 2 ,MEF2 Transcription Factors ,Lipid metabolism ,HDAC4 ,HDAC5 ,Lipid Metabolism ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,lcsh:Biology (General) ,Mutation ,Quinolines ,Histone deacetylase ,MEF2 ,Energy Metabolism ,Corepressor ,Co-Repressor Proteins ,Oxidation-Reduction ,Protein Binding - Abstract
SummaryDrugs 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.
- Published
- 2016