线粒体是细胞能量代谢和信息交换的中心，其质量状态受到精密的监测。骨骼肌线粒体质量衰退，引发肌细胞代谢紊乱，是代谢疾病发生的重要因素。然而关于骨骼肌线粒体质量控制的调节机制还不清楚。我们曾发现miR-499/Fnip1通路将线粒体功能与肌纤维结构紧密偶联。通过研究miR-499转基因和Fnip1基因敲除小鼠实验初步证实，miR-499能抵抗年老引起的线粒体退行性改变，并且抵抗老年肥胖；此外，Fnip1还可抑制骨骼肌AMPK线粒体质量控制通路。因此，我们提出：miR-499/Fnip1通路可能通过调节骨骼肌线粒体质量，在机体代谢稳态调节中发挥重要作用。为证实这一假设，本课题将分别从整体水平、细胞水平和线粒体亚细胞水平剖析miR-499/Fnip1通路在骨骼肌线粒体质量控制和代谢疾病中的功能及其作用过程，提出一个Fnip1线粒体通路对机体代谢平衡的调节模式，为代谢疾病的防治新途径提供实验依据。

Mitochondria are the centers of cell energy metabolism and signaling cross-talk. The quality of mitochondria must be precisely monitored to maintain cell function. Skeletal muscle mitochondrial dysfunction, leads to malfunction of cell metabolism, is an important causing factor for many metabolic diseases. However, the molecular mechanism underlying the regulation of muscle mitochondrial homeostasis is unclear. Our previous work demonstrated that miR-499/Fnip1 pathway couples mitochondrial function to muscle fiber type. Using muscle-specific miR-499 transgenic and Fnip1 knockout mice, our preliminary data suggest that miR-499 can prevent skeletal muscle metabolic and structural degenerative changes during aging, and miR-499Tg mice are resistant to age-associated insulin resistance and obesity; Moreover, Fnip1 is a potent inhibitor of muscle AMPK/mitochondrial quality signaling. Together with previous reports and our preliminary observations, we propose that miR-499/Fnip1 pathway is a key regulator of muscle mitochondrial homeostasis, may therefore play a very important role in regulating metabolic diseases. To verify this hypothesis, we will analyze a series of animal model with physiological, molecular and cellular methods to elucidate the mechanistic actions of miR-499/Fnip1 axis in mitochondrial quality control and metabolic disorders. Completion of this project will provide with experimental instructions for new therapeutic strategies aimed at maintaining muscle mitochondria quality in a variety of metabolic diseases.