Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation.
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.
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia.
Vidhi
V
Gaur
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia.
Timothy
T
Connor
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia.
Andrew
A
Sanigorski
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia.
Sheree D
SD
Martin
School of Exercise and Nutrition Sciences, Deakin University, Burwood, VIC 3125, Australia.
Clinton R
CR
Bruce
Metabolism and Inflammation Program, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Darren C
DC
Henstridge
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia.
Simon T
ST
Bond
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia.
Kevin A
KA
McEwen
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia.
Lyndal
L
Kerr-Bayles
Research Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, VIC 3216, Australia.
Trent D
TD
Ashton
Research Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, VIC 3216, Australia.
Cassandra
C
Fleming
Seahorse Bioscience, North Billerica, MA 01862, USA.
Min
M
Wu
Seahorse Bioscience, North Billerica, MA 01862, USA.
Lisa S
LS
Pike Winer
Seahorse Bioscience, North Billerica, MA 01862, USA.
Denise
D
Chen
Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester LE1 7RH, UK.
Gregg M
GM
Hudson
Department of Biochemistry, Henry Wellcome Laboratories of Structural Biology, University of Leicester, Leicester LE1 7RH, UK.
John W R
JWR
Schwabe
Department of Neurobiology, Physiology and Behavior and Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA.
Keith
K
Baar
Metabolism and Inflammation Program, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Division of Diabetes & Metabolism, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
Mark A
MA
Febbraio
Muscle Research and Therapeutics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Paul
P
Gregorevic
Research Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, VIC 3216, Australia.
Frederick M
FM
Pfeffer
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia.
Ken R
KR
Walder
Department of Physiology, The University of Melbourne, Parkville, VIC 3010, Australia.
Mark
M
Hargreaves
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia; Metabolism and Inflammation Program, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia. Electronic address: sean.mcgee@deakin.edu.au.
Sean L
SL
McGee
D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D056970:Co-Repressor Proteins / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism*; D006898:Hydroxylamines / Q000008:administration & dosage / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D010805:Physical Conditioning, Animal; D011485:Protein Binding / Q000187:drug effects; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D056970:Co-Repressor Proteins; D006898:Hydroxylamines; D064326:MEF2 Transcription Factors; D011804:Quinolines; C410733:scriptaid; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
HDAC4; HDAC5; MEF2; Skeletal muscle