Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy.
Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy.
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作者：
核受体Rev-erb-α调节肝脏脂质和葡萄糖代谢、脂肪生成和巨噬细胞的炎症反应。我们发现Rev-erb-α在氧化骨骼肌中高度表达，并在功能获得和丧失研究中在线粒体生物发生和氧化功能中发挥作用。骨骼肌中的Rev-erb-α-缺乏导致线粒体含量和氧化功能降低，导致运动能力受损。这种表型在Rev-erbα敲低后在分离的纤维和肌细胞中重现，而Rev-erb-α过表达增加了线粒体的数量，改善了呼吸能力。Rev-erb-α缺陷导致Stk 11-Ampk-Sirt 1-Ppargc 1-α信号通路失活，而自噬上调，导致线粒体生物合成受损和清除率增加。肌肉过度表达或药理学激活Rev-erb-α可增加呼吸和运动能力。本研究将Rev-erb-α确定为通过调节控制线粒体数量和功能的基因网络来改善肌肉氧化功能的药理学靶点。
The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α is highly expressed in oxidative skeletal muscle and plays a role in mitochondrial biogenesis and oxidative function, in gain- and loss-of function studies. Rev-erb-α-deficiency in skeletal muscle leads to reduced mitochondrial content and oxidative function, resulting in compromised exercise capacity. This phenotype was recapitulated in isolated fibers and in muscle cells upon Rev-erbα knock-down, while Rev-erb-α over-expression increased the number of mitochondria with improved respiratory capacity. Rev-erb-α-deficiency resulted in deactivation of the Stk11–Ampk–Sirt1–Ppargc1-α signaling pathway, whereas autophagy was up-regulated, resulting in both impaired mitochondrial biogenesis and increased clearance. Muscle over-expression or pharmacological activation of Rev-erb-α increased respiration and exercise capacity. This study identifies Rev-erb-α as a pharmacological target which improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.
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DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
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影响因子：
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DOI：
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发表时间：
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影响因子：
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DOI：
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发表时间：
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期刊：
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