Institut Pasteur de Lille, Lille, France.
Nat Med. 2013 Aug;19(8):1039-46. doi: 10.1038/nm.3213. Epub 2013 Jul 14.
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 that its deficiency in muscle leads to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy. These cellular effects resulted in both impaired mitochondrial biogenesis and increased clearance of this organelle, leading to compromised exercise capacity. On a molecular level, Rev-erb-α deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1-Ppargc-1α signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-α, Nr1d1. In complementary experiments, Rev-erb-α overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-α in vivo increased exercise capacity. This study identifies Rev-erb-α as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.
核受体 Rev-erb-α 调节肝脏脂质和葡萄糖代谢、脂肪生成以及巨噬细胞中的炎症反应。我们在此表明，Rev-erb-α 在氧化骨骼肌中高度表达，其在肌肉中的缺乏导致线粒体含量和氧化功能减少，以及自噬上调。这些细胞效应导致线粒体生物发生受损和该细胞器的清除增加，从而导致运动能力受损。在分子水平上，Rev-erb-α 的缺乏导致 Lkb1-Ampk-Sirt1-Ppargc-1α 信号通路失活。Nr1d1 基因编码的 Rev-erb-α 敲低后，在分离的纤维和肌肉细胞中重现了这些效应。在补充实验中，体外过表达 Rev-erb-α 增加了线粒体的数量并改善了呼吸能力，而体内肌肉过表达或药理学激活 Rev-erb-α 则增加了运动能力。这项研究确定了 Rev-erb-α 是一种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物靶点。
