title: Compensatory regulation of HDAC5 in muscle maintains metabolic adaptive responses and metabolism in response to energetic stress.
abstract: Some gene deletions or mutations have little effect on metabolism and metabolic adaptation because of redundancy and/or compensation in metabolic pathways. The mechanisms for redundancy and/or compensation in metabolic adaptation in mammalian cells are unidentified. Here, we show that in mouse muscle and myogenic cells, compensatory regulation of the histone deacetylase (HDAC5) transcriptional repressor maintains metabolic integrity. HDAC5 phosphorylation regulated the expression of diverse metabolic genes and glucose metabolism in mouse C2C12 myogenic cells. However, loss of AMP-activated protein kinase (AMPK), a HDAC5 kinase, in muscle did not affect HDAC5 phosphorylation in mouse skeletal muscle during exercise, but resulted in a compensatory increase (32.6%) in the activation of protein kinase D (PKD), an alternate HDAC5 kinase. Constitutive PKD activation in mouse C2C12 myogenic cells regulated metabolic genes and glucose metabolism. Although aspects of this response were HDAC5 phosphorylation dependent, blocking HDAC5 phosphorylation when PKD was active engaged an alternative compensatory adaptive mechanism, which involved post-transcriptional reductions in HDAC5 mRNA (-93.1%) and protein. This enhanced the expression of a specific subset of metabolic genes and mitochondrial metabolism. These data show that compensatory regulation of HDAC5 maintains metabolic integrity in mammalian cells and reinforces the importance of preserving the cellular metabolic adaptive response.
authors.affiliation: Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia; Division of Cell Signalling and Metabolism, Baker International Diabetes Institute Heart and Diabetes Institute, Melbourne, Victoria, Australia; sean.mcgee@deakin.edu.au.
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
authors.affiliation: Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia;
authors.forename: Courtney
authors.initials: C
authors.lastname: Swinton
authors.affiliation: Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia;
authors.forename: Shona
authors.initials: S
authors.lastname: Morrison
authors.affiliation: Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia;
authors.forename: Vidhi
authors.initials: V
authors.lastname: Gaur
authors.affiliation: Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia; Department of Physiology, The University of Melbourne, Parkville, Victoria, Australia;
authors.forename: Duncan E
authors.initials: DE
authors.lastname: Campbell
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia; Diabetes Research Unit, Novo Nordisk A/S, Maaloev, Denmark;
authors.forename: Sebastian B
authors.initials: SB
authors.lastname: Jorgensen
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia;
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.affiliation: Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California, USA; and.
authors.forename: Keith
authors.initials: K
authors.lastname: Baar
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.affiliation: Department of Physiology, The University of Melbourne, Parkville, Victoria, Australia;
authors.forename: M
authors.initials: M
authors.lastname: Hargreaves
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000502:physiology; D000107:Acetylation; D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D004734:Energy Metabolism / Q000502:physiology*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000201:enzymology*; D032446:Myoblasts / Q000378:metabolism*; D010766:Phosphorylation; D010805:Physical Conditioning, Animal / Q000502:physiology*; D017354:Point Mutation; D011493:Protein Kinase C / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D019076:Transgenes
chemical_list: D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C089212:protein kinase D; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases; C404500:HDAC5 protein, human; D006655:Histone Deacetylases; D005947:Glucose
keywords: AMP-activated protein kinase; exercise; protein kinase D; skeletal muscle