SIRT6 regulates metabolic homeostasis in skeletal muscle through activation of AMPK
SIRT6 regulates metabolic homeostasis in skeletal muscle through activation of AMPK
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SIRT6 通过激活 AMPK 来调节骨骼肌的代谢稳态。
DOI：
10.1152/ajpendo.00122.2017
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发表时间：
2017-10-01
影响因子：
5.1
通讯作者：
Chang, Yongsheng
中科院分区：
文献类型：
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作者：
Cui, Xiaona;Yao, Lu;Chang, Yongsheng
由于骨骼肌的质量和代谢功能，骨骼肌是调节全身代谢稳态的主要器官之一。SIRT 6是一种组蛋白脱乙酰酶，已被证明可调节肝脏和大脑中的代谢;然而，其在骨骼肌中的具体作用尚未确定。本研究探讨了SIRT 6在肌肉中的生理功能。我们产生了肌肉特异性SIRT 6敲除小鼠模型。肌肉中SIRT 6缺乏的小鼠表现出葡萄糖稳态和胰岛素敏感性受损，全身能量消耗减弱，运动能力减弱。从机制上讲，肌肉中SIRT 6的缺失降低了参与肌肉细胞中葡萄糖和脂质摄取、脂肪酸氧化和线粒体氧化磷酸化的基因的表达，因为AMP活化蛋白激酶（AMPK）活性降低。相反，C2 C12肌管中SIRT 6的过表达激活AMPK。我们从功能获得和功能丧失实验的结果将SIRT 6鉴定为肌肉线粒体功能的生理调节剂。这些发现表明SIRT 6是治疗2型糖尿病的潜在治疗靶点。
Because of the mass and functions in metabolism, skeletal muscle is one of the major organs regulating whole body metabolic homeostasis. SIRT6, a histone deacetylase, has been shown to regulate metabolism in liver and brain; however, its specific role in skeletal muscle is undetermined. In the present study we explored physiological function of SIRT6 in muscle. We generated a muscle-specific SIRT6 knockout mouse model. The mice with SIRT6 deficiency in muscle displayed impaired glucose homeostasis and insulin sensitivity, attenuated whole body energy expenditure, and weakened exercise performance. Mechanistically, deletion of SIRT6 in muscle decreased expression of genes involved in glucose and lipid uptake, fatty acid oxidation, and mitochondrial oxidative phosphorylation in muscle cells because of the reduced AMP-activated protein kinase (AMPK) activity. In contrast, overexpression of SIRT6 in C2C12 myotubes activates AMPK. Our results from both gain- and loss-of-function experiments identify SIRT6 as a physiological regulator of muscle mitochondrial function. These findings indicate that SIRT6 is a potential therapeutic target for treatment of type 2 diabetes mellitus.