title: HC toxin (a HDAC inhibitor) enhances IRS1-Akt signalling and metabolism in mouse myotubes.
abstract: Exercise enhances numerous signalling pathways and activates substrate metabolism in skeletal muscle. Small molecule compounds that activate these cellular responses have been shown to recapitulate the metabolic benefits of exercise. In this study, a histone deacetylase (HDAC) inhibitor, HC toxin, was investigated as a small molecule compound that activates exercise-induced adaptations. In C2C12 myotubes, HC toxin treatment activated two exercise-stimulated pathways: AMP-activated protein kinase (AMPK) and Akt pathways. HC toxin increased the protein content and phosphorylation of insulin receptor substrate 1 as well as the activation of downstream Akt signalling. The effects of HC toxin on IRS1-Akt signalling were PI3K-dependent as wortmannin abolishes its effects on IRS1 protein accumulation and Akt phosphorylation. HC toxin-induced Akt activation was sufficient to enhance downstream mTOR complex 1 (mTORC1) signalling including p70S6K and S6, which were consistently abolished by PI3K inhibition. Insulin-stimulated glucose uptake, glycolysis, mitochondrial respiration and fatty acid oxidation were also enhanced in HC toxin-treated myotubes. When myotubes were challenged with serum starvation for the induction of atrophy, HC toxin treatment prevented the induction of genes that are involved in autophagy and proteasomal proteolysis. Conversely, IRS1-Akt signalling was not induced by HC toxin in several hepatoma cell lines, providing evidence for a favourable safety profile of this small molecule. These data highlight the potential of HDAC inhibitors as a novel class of small molecules for the induction of exercise-like signalling pathways and metabolism.
authors.affiliation: Department of BiochemistryYong Loo Lin School of Medicine, National University of Singapore, Block MD 7, 8 Medical Drive, #03-08, Singapore 117597, SingaporeState Key Laboratory of Drug ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hayden Weng Siong
authors.initials: HW
authors.lastname: Tan
authors.affiliation: Department of BiochemistryYong Loo Lin School of Medicine, National University of Singapore, Block MD 7, 8 Medical Drive, #03-08, Singapore 117597, SingaporeState Key Laboratory of Drug ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Arthur Yi Loong
authors.initials: AY
authors.lastname: Sim
authors.affiliation: Department of BiochemistryYong Loo Lin School of Medicine, National University of Singapore, Block MD 7, 8 Medical Drive, #03-08, Singapore 117597, SingaporeState Key Laboratory of Drug ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Su Ling
authors.initials: SL
authors.lastname: Huang
authors.affiliation: Department of BiochemistryYong Loo Lin School of Medicine, National University of Singapore, Block MD 7, 8 Medical Drive, #03-08, Singapore 117597, SingaporeState Key Laboratory of Drug ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Leng
authors.affiliation: Department of BiochemistryYong Loo Lin School of Medicine, National University of Singapore, Block MD 7, 8 Medical Drive, #03-08, Singapore 117597, SingaporeState Key Laboratory of Drug ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China bchlongy@nus.edu.sg.
authors.forename: Yun Chau
authors.initials: YC
authors.lastname: Long
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001284:Atrophy / Q000188:drug therapy / Q000235:genetics; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D010101:Oxygen Consumption; D010456:Peptides, Cyclic / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D055372:AMP-Activated Protein Kinases; D005947:Glucose; D056572:Histone Deacetylase Inhibitors; D055504:Insulin Receptor Substrate Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D010456:Peptides, Cyclic; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C526295:Irs1 protein, mouse; C037654:HC toxin
keywords: Akt; exercise; histone deacetylase (HDAC); insulin receptor substrate 1 (IRS1); metabolism; myotubes