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The HDAC3 enzymatic activity regulates skeletal muscle fuel metabolism

Journal of Molecular Cell Biology 2019年第2期11卷 133-143页

作者： Shiyan Song Yefei Wen Hui Tong emanuele loro Yingyun Gong Jidong Liu Sungguan Hong Lei Li Tejvir S.Khurana Maoping Chu Zheng Sun Children's Heart Center The Second Affiliated Hospital and Yuying Children's Hospital Institute of Cardiovascular Development and Translational MedicineWenzhou 325027 China Division of Endocrinology Diabetes and Metabolism Department of Medicine Baylor College of Medicine Houston TX 77030 USA Department of Physiology and Pennsylvania Muscle Institute Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA Department of Chemistry Chung-Ang University Seoul Korea Department of Molecular and Cellular Biology Baylor College of Medicine Houston TX 77030 USA

Histone deacetylase 3 (HDAC3) is a major HDAC, whose enzymatic activity is targeted by small molecule inhibitors for treating a variety of conditions. However, its enzymatic activity is largely dispensable for its function in embryonic development and hepatic lipid ***3 plays a pivotal role in regulating muscle fuel metabolism and contractile function. Here, we address whether these muscular functions of HDAC3 require its enzymatic activity. By mutating the NCoR/SMRT corepressors in a knock - in mouse model named NS-DADm, we ablated the enzymatic activity of HDAC3 without affecting its protein levels. Compared to the control mice, skeletal muscles from NS-DADm mice showed lower force generation, enhanced fatigue resistance, enhanced fatty acid oxidation, reduced glucose uptake during exercise, upregulated expression of metabolic genes involved in branchedchain amino acids catabolism, and reduced muscle mass during aging, without changes in the muscle fiber-type composition or mitochondrial protein content. These muscular phenotypes are similar to those observed in the HDAC3-depleted skeletal muscles, which demonstrates that, unlike that in the liver or embryonic development, the metabolic function of HDAC3 in skeletal muscles requires its enzymatic activity. These results suggest that drugs specifically targeting HDAC3 enzyme activity could be developed and tested to modulate muscle energy metabolism and exercise performance.

关键词： HDAC muscle metabolism nuclear receptor corepressor histone deacetylation

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The HDAC3 Enzyme Activity Regulates Skeletal Muscle Fuel Metabolism

The HDAC3 Enzyme Activity Regulates Skeletal Muscle Fuel Met...

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2018年浙江省医学会儿科学分会学术年会

作者： Shiyang Song Yefei Wen Hui Tong emanuele loro Ying-Wooi Wan Yingyun Gong Jidong Liu Tejvir S.Khurana ZhANDong Liu Zheng Sun Division of Endocrinology Diabetesand MetabolismDepartment of MedicineBaylor College of Medicine Department of Physiology Perelman School of MedicineUniversity of Pennsylvania Department of Pediatrics Jan and Dan Duncan Neurological Research InstituteBaylor College of Medicine Department of Molecular and Cellular Biology Baylor College of Medicine

Histone deacetylase 3 (HDAC3) is a major HDAC whose enzyme activity is targeted by many small molecule HDAC inhibitors for treating a variety of conditions,but its enzyme activity is largely dispensable for its function in embryonic development and liver lipid *** AC 3 plays a pivotal role in regulating muscle insulin sensitivity and exercise *** we address whether the function of HDAC3 in skeletal muscles requires its enzyme ***3 gains its activity through binding to the Deacetylase Activation Domain (DAD) of theNuclear Receptor Co-repressors (NCORs).

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