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 L. 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 & 3 others Ken R Walder, Mark Hargreaves, Sean L McGee

Research output: Contribution to journalArticleResearchpeer-review

29 Citations (Scopus)

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
Pages (from-to)2802-2810
Number of pages9
JournalCell Reports
Volume16
Issue number11
DOIs
Publication statusPublished - 13 Sep 2016
Externally publishedYes

Keywords

  • HDAC4
  • HDAC5
  • MEF2
  • Skeletal muscle

Cite this

Gaur, Vidhi ; Connor, Timothy ; Sanigorski, Andrew ; Martin, Sheree D ; Bruce, Clinton R. ; Henstridge, Darren C. ; Bond, Simon T. ; McEwen, Kevin A. ; Kerr-Bayles, Lyndal ; Ashton, Trent D. ; Fleming, Cassandra L. ; Wu, Min ; Pike Winer, Lisa S. ; Chen, Denise ; Hudson, Gregg M. ; Schwabe, John W R ; Baar, Keith ; Febbraio, Mark A. ; Gregorevic, Paul ; Pfeffer, Frederick M. ; Walder, Ken R ; Hargreaves, Mark ; McGee, Sean L. / Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation. In: Cell Reports. 2016 ; Vol. 16, No. 11. pp. 2802-2810.
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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.",
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Gaur, V, Connor, T, Sanigorski, A, Martin, SD, Bruce, CR, Henstridge, DC, Bond, ST, McEwen, KA, Kerr-Bayles, L, Ashton, TD, Fleming, CL, Wu, M, Pike Winer, LS, Chen, D, Hudson, GM, Schwabe, JWR, Baar, K, Febbraio, MA, Gregorevic, P, Pfeffer, FM, Walder, KR, Hargreaves, M & McGee, SL 2016, 'Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation', Cell Reports, vol. 16, no. 11, pp. 2802-2810. https://doi.org/10.1016/j.celrep.2016.08.005

Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation. / Gaur, Vidhi; Connor, Timothy; Sanigorski, Andrew; Martin, Sheree D; Bruce, Clinton R.; Henstridge, Darren C.; Bond, Simon T.; McEwen, Kevin A.; Kerr-Bayles, Lyndal; Ashton, Trent D.; Fleming, Cassandra L.; Wu, Min; Pike Winer, Lisa S.; Chen, Denise; Hudson, Gregg M.; Schwabe, John W R; Baar, Keith; Febbraio, Mark A.; Gregorevic, Paul; Pfeffer, Frederick M.; Walder, Ken R; Hargreaves, Mark; McGee, Sean L.

In: Cell Reports, Vol. 16, No. 11, 13.09.2016, p. 2802-2810.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation

AU - Gaur, Vidhi

AU - Connor, Timothy

AU - Sanigorski, Andrew

AU - Martin, Sheree D

AU - Bruce, Clinton R.

AU - Henstridge, Darren C.

AU - Bond, Simon T.

AU - McEwen, Kevin A.

AU - Kerr-Bayles, Lyndal

AU - Ashton, Trent D.

AU - Fleming, Cassandra L.

AU - Wu, Min

AU - Pike Winer, Lisa S.

AU - Chen, Denise

AU - Hudson, Gregg M.

AU - Schwabe, John W R

AU - Baar, Keith

AU - Febbraio, Mark A.

AU - Gregorevic, Paul

AU - Pfeffer, Frederick M.

AU - Walder, Ken R

AU - Hargreaves, Mark

AU - McGee, Sean L

PY - 2016/9/13

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N2 - 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.

AB - 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.

KW - HDAC4

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KW - MEF2

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