posted on 2016-11-09, 12:34authored byV. Gaur, T. Connor, A. Sanigorski, S. D. Martin, C. R. Bruce, D. C. Henstridge, S. T. Bond, K. A. McEwen, L. Kerr-Bayles, T. D. Ashton, C. Fleming, M. Wu, L. S. P. Winer, D. Chen, Gregg M. Hudson, John W. R. Schwabe, K. Baar, M. A. Febbraio, P. Gregorevic, F. M. Pfeffer, K. R. Walder, M. Hargreaves, S. L. McGee
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.
Funding
This research was supported by the Diabetes Australia Research Trust Viertel Award and by grants from the National Health and Medical Research Council (NHMRC) of Australia (1027727) and the Deakin University Molecular and Medical Research Strategic Research Centre to S.L.M. J.W.R.S. is supported by Wellcome Trust Senior Investigator Award WT100237 and is a Royal Society Merit Award Holder. M.A.F., P.G., and S.L.M. are supported by research fellowships from the NHMRC.
History
Citation
Cell Reports, 2016, 16 (11), pp. 2802-2810 (9)
Author affiliation
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell Biology