Coupling of mitochondrial function and skeletal muscle fiber type by a miR-499/Fnip1/AMPK circuit

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• 作者：Jing Liu ; Xijun Liang ; Danxia Zhou ; Ling Lai ; Liwei Xiao ; Lin Liu ; Tingting Fu ; Yan Kong ; Qian Zhou ; Rick B Vega ; Min-Sheng Zhu ; Daniel P Kelly ; Xiang Gao and Zhenji Gan
• 刊名：EMBO Molecular Medicine
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：8
• 期：10
• 页码：1212-1228
• 全文大小：3014K
• ISSN：1757-4684

文摘

Upon adaption of skeletal muscle to physiological and pathophysiological stimuli, muscle fiber type and mitochondrial function are coordinately regulated. Recent studies have identified pathways involved in control of contractile proteins of oxidative-type fibers. However, the mechanism for coupling of mitochondrial function to the muscle contractile machinery during fiber type transition remains unknown. Here, we show that the expression of the genes encoding type I myosins, Myh7/Myh7b and their intronic miR-208b/miR-499, parallels mitochondrial function during fiber type transitions. Using in vivo approaches in mice, we found that miR-499 drives a PGC-1α-dependent mitochondrial oxidative metabolism program to match shifts in slow-twitch muscle fiber composition. Mechanistically, miR-499 directly targets Fnip1, an AMP-activated protein kinase (AMPK)-interacting protein that negatively regulates AMPK, a known activator of PGC-1α. Inhibition of Fnip1 reactivated AMPK/PGC-1α signaling and mitochondrial function in myocytes. Restoration of the expression of miR-499 in the mdx mouse model of Duchenne muscular dystrophy (DMD) reduced the severity of DMD. Thus, we have identified a miR-499/Fnip1/AMPK circuit that can serve as a mechanism to couple muscle fiber type and mitochondrial function.