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. Pfeffer,
Ken R. Walder,
Mark Hargreaves,
Sean L. McGee
Affiliations
Vidhi Gaur
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
Timothy Connor
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
Andrew Sanigorski
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
Sheree D. Martin
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
Clinton R. Bruce
School of Exercise and Nutrition Sciences, Deakin University, Burwood, VIC 3125, Australia
Darren C. Henstridge
Metabolism and Inflammation Program, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
Simon T. Bond
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
Kevin A. McEwen
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
Lyndal Kerr-Bayles
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
Trent D. Ashton
Research Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, VIC 3216, Australia
Cassandra Fleming
Research Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, VIC 3216, Australia
Min Wu
Seahorse Bioscience, North Billerica, MA 01862, USA
Lisa S. Pike Winer
Seahorse Bioscience, North Billerica, MA 01862, USA
Denise Chen
Seahorse Bioscience, North Billerica, MA 01862, USA
Gregg M. Hudson
Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester LE1 7RH, UK
John W.R. Schwabe
Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester LE1 7RH, UK
Keith Baar
Department of Neurobiology, Physiology and Behavior and Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA
Mark A. Febbraio
Metabolism and Inflammation Program, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
Paul Gregorevic
Muscle Research and Therapeutics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
Frederick M. Pfeffer
Research Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, VIC 3216, Australia
Ken R. Walder
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
Mark Hargreaves
Department of Physiology, The University of Melbourne, Parkville, VIC 3010, Australia
Sean L. McGee
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
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.
