The HDAC3 enzymatic activity regulates skeletal muscle fuel metabolism

被引:31
|
作者
Song, Shiyang [1 ,2 ,3 ]
Wen, Yefei [3 ]
Tong, Hui [3 ]
Loro, Emanuele [4 ,5 ]
Gong, Yingyun [3 ]
Liu, Jidong [3 ]
Hong, Sungguan [3 ,6 ]
Li, Lei [1 ,2 ]
Khurana, Tejvir S. [4 ,5 ]
Chu, Maoping [1 ,2 ]
Sun, Zheng [3 ,7 ]
机构
[1] Second Affiliated Hosp, Childrens Heart Ctr, Wenzhou 325027, Peoples R China
[2] Yuying Childrens Hosp, Inst Cardiovasc Dev & Translat Med, Wenzhou 325027, Peoples R China
[3] Baylor Coll Med, Div Endocrinol Diabet & Metab, Dept Med, Houston, TX 77030 USA
[4] Univ Penn, Perelman Sch Med, Dept Physiol, Philadelphia, PA 19104 USA
[5] Univ Penn, Perelman Sch Med, Penn Muscle Inst, Philadelphia, PA 19104 USA
[6] Chung Ang Univ, Dept Chem, Seoul, South Korea
[7] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
基金
美国国家卫生研究院; 中国国家自然科学基金;
关键词
HDAC; muscle metabolism; nuclear receptor corepressor; histone deacetylation; HISTONE DEACETYLASE 3; NUCLEAR RECEPTOR COREPRESSOR; EXERCISE PERFORMANCE; CO-REPRESSOR; FIBER-TYPE; STEM-CELL; PGC-1-ALPHA; ALPHA; SMRT; TRANSCRIPTION;
D O I
10.1093/jmcb/mjy066
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 metabolism. HDAC3 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 branched-chain 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.
引用
收藏
页码:133 / 143
页数:11
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