The HDAC3 Enzymatic Activity Regulates Skeletal Muscle Fuel Metabolism

We address whether the functions of HDAC3 in skeletal muscle require its enzyme 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 (BCAAs) catabolism, and aging-associated reduction in muscle mass, without changes in the muscle fiber type composition or mitochondrial protein content. These findings demonstrate that the metabolic function of HDAC3 in skeletal muscles requires its enzymatic activity. examination of 3 different samples in each genotype (WT and NS-DADm)本研究旨在探究骨骼肌中组蛋白去乙酰化酶3（HDAC3）的功能是否依赖其酶促活性。本研究通过在命名为NS-DADm的敲入小鼠模型中对NCoR/SMRT共抑制因子进行突变，在不改变HDAC3蛋白表达水平的前提下，敲除了其酶促活性。与对照小鼠相比，NS-DADm小鼠的骨骼肌表现出肌力生成降低、抗疲劳能力增强、脂肪酸氧化水平提升、运动过程中葡萄糖摄取减少、支链氨基酸（BCAAs）分解代谢相关代谢基因的表达上调，以及衰老相关的肌肉量减少，而肌纤维类型组成与线粒体蛋白含量未发生改变。上述研究结果表明，骨骼肌中HDAC3的代谢功能依赖于其酶促活性。本研究对每种基因型（野生型WT与NS-DADm）的3份不同样本开展了检测分析。