HC toxin (a HDAC inhibitor) enhances IRS1-Akt signalling and metabolism in mouse myotubes

doi:10.1530/JME-15-0140

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	HC toxin (a HDAC inhibitor) enhances IRS1-Akt signalling and metabolism in mouse myotubes
	Tan, Hayden Weng Siong 1; Sim, Arthur Yi Loong 1; Huang, Su Ling 2; Leng, Ying2 ; Long, Yun Chau 1
刊名	JOURNAL OF MOLECULAR ENDOCRINOLOGY
	2015-12
卷号	55 期号:3 页码:197-207
关键词	histone deacetylase (HDAC) Akt insulin receptor substrate 1 (IRS1) metabolism exercise myotubes
ISSN号	0952-5041
DOI	10.1530/JME-15-0140
文献子类	Article
英文摘要	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.
资助项目	National Medical Research Council (NMRC), Singapore (NMRC/BNIG)[00000000] ; Singapore Ministry of Education Academic Research Fund[00000000]
WOS关键词	INSULIN-RECEPTOR SUBSTRATE-1 ; STIMULATED GLUCOSE-UPTAKE ; ACTIVATED PROTEIN-KINASE ; SKELETAL-MUSCLE ATROPHY ; HISTONE DEACETYLASES ; RESISTANCE EXERCISE ; MESSENGER-RNA ; MICE ; CELLS ; PHOSPHORYLATION
WOS研究方向	Endocrinology & Metabolism
语种	英语
出版者	BIOSCIENTIFICA LTD
WOS记录号	WOS:000365033800008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276312]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Long, Yun Chau
作者单位	1.Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117597, Singapore; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Tan, Hayden Weng Siong,Sim, Arthur Yi Loong,Huang, Su Ling,et al. HC toxin (a HDAC inhibitor) enhances IRS1-Akt signalling and metabolism in mouse myotubes[J]. JOURNAL OF MOLECULAR ENDOCRINOLOGY,2015,55(3):197-207.
APA	Tan, Hayden Weng Siong,Sim, Arthur Yi Loong,Huang, Su Ling,Leng, Ying,&Long, Yun Chau.(2015).HC toxin (a HDAC inhibitor) enhances IRS1-Akt signalling and metabolism in mouse myotubes.JOURNAL OF MOLECULAR ENDOCRINOLOGY,55(3),197-207.
MLA	Tan, Hayden Weng Siong,et al."HC toxin (a HDAC inhibitor) enhances IRS1-Akt signalling and metabolism in mouse myotubes".JOURNAL OF MOLECULAR ENDOCRINOLOGY 55.3(2015):197-207.