Coupling of mitochondrial function and skeletal muscle fiber type by a miR-499/Fnip1/AMPK circuit.
Coupling of mitochondrial function and skeletal muscle fiber type by a miR-499/Fnip1/AMPK circuit.
复制标题
通过 miR-499/Fnip1/AMPK 电路耦合线粒体功能和骨骼肌纤维类型。
DOI：
10.15252/emmm.201606372
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发表时间：
2016-10
影响因子：
11.1
通讯作者：
Gan Z
中科院分区：
文献类型：
--
作者：
Liu J;Liang X;Zhou D;Lai L;Xiao L;Liu L;Fu T;Kong Y;Zhou Q;Vega RB;Zhu MS;Kelly DP;Gao X;Gan Z
在骨骼肌适应生理和病理生理刺激后，肌纤维类型和线粒体功能受到协调调节。最近的研究已经确定了参与氧化型纤维收缩蛋白控制的途径。然而，在纤维类型转换过程中线粒体功能与肌肉收缩机制的耦合机制仍然未知。在这里，我们表明，编码I型肌球蛋白，Myh 7/Myh 7 b和它们的内含子miR-208 b/miR-499的基因的表达，在纤维类型转换过程中与线粒体功能平行。使用小鼠体内方法，我们发现miR-499驱动PGC-1α依赖性线粒体氧化代谢程序，以匹配慢收缩肌纤维组成的变化。从机制上讲，miR-499直接靶向Fnip 1，这是一种AMP活化蛋白激酶（AMPK）相互作用蛋白，可负调节AMPK，一种已知的PGC-1α激活剂。Fnip 1的抑制重新激活了AMPK/PGC-1α信号传导和肌细胞中的线粒体功能。在Duchenne肌营养不良症（DMD）mdx小鼠模型中恢复miR-499的表达可降低DMD的严重程度。因此，我们已经确定了一个miR-499/Fnip 1/AMPK回路，可以作为一种机制，耦合肌纤维类型和线粒体功能。
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.