Mitochondrial Dysfunction Launches Dexamethasone-Induced Skeletal Muscle Atrophy via AMPK/FOXO3 Signaling
Mitochondrial Dysfunction Launches Dexamethasone-Induced Skeletal Muscle Atrophy via AMPK/FOXO3 Signaling
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DOI：
10.1021/acs.molpharmaceut.5b00516
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发表时间：
2016-01-01
影响因子：
4.9
通讯作者：
Liu, Jiankang
中科院分区：
文献类型：
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作者：
Liu, Jing;Peng, Yunhua;Liu, Jiankang
肌肉萎缩发生在几种病理条件下，如糖尿病和慢性阻塞性肺病（COPD），以及在长期临床施用合成的糖皮质激素后，其中增加的循环糖皮质激素是肌肉萎缩的发病机制。其他人和我们先前报道了与肌肉萎缩相关的疾病中的线粒体功能障碍，并且补充营养素有效地预防了各种肌肉萎缩。然而，线粒体功能障碍是否以及如何涉及糖皮质激素诱导的肌肉萎缩仍不清楚。因此，在本研究中，我们在体内和体外测量了地塞米松诱导的肌肉萎缩中的线粒体功能，我们发现地塞米松给药后第3天线粒体呼吸受损，早于MuRF 1和Fbx 32的增加，以及地塞米松诱导的线粒体组分和关键线粒体动力学蛋白的丢失。此外，地塞米松治疗引起细胞内ATP剥夺和强大的AMPK激活，这进一步激活FOXO 3/Atrogenes途径。通过直接损害线粒体呼吸，FCCP导致C2 C12肌管中与地塞米松类似的读数。相反，白藜芦醇，一种线粒体营养素，通过改善线粒体功能和阻断AMPK/FOXO 3信号传导，有效地逆转了地塞米松诱导的C2 C12肌管和小鼠的线粒体功能障碍和肌肉萎缩。这些结果表明，线粒体功能障碍在地塞米松诱导的骨骼肌萎缩中起着核心作用，靶向线粒体的营养物质或药物可能有助于预防或治疗肌肉萎缩。
Muscle atrophy occurs in several pathologic conditions such as diabetes and chronic obstructive pulmonary disease (COPD), as well as after long-term clinical administration of synthesized glucocorticoid, where increased circulating glucocorticoid accounts for the pathogenesis of muscle atrophy. Others and we previously reported mitochondrial dysfunction in muscle atrophy-related conditions and that mitochondriatargeting nutrients efficiently prevent kinds of muscle atrophy. However, whether and how mitochondrial dysfunction involves glucocorticoid-induced muscle atrophy remains unclear. Therefore, in the present study, we measured mitochondrial function in dexamethasoneinduced muscle atrophy in vivo and in vitro, and we found that mitochondrial respiration was compromised on the 3(rd) day following after dexamethasone administration, earlier than the increases of MuRF1 and Fbx32, and dexamethasone-induced loss of mitochondrial components and key mitochondrial dynamics proteins. Furthermore, dexamethasone treatment caused intracellular ATP deprivation and robust AMPK activation, which further activated the FOXO3/Atrogenes pathway. By directly impairing mitochondrial respiration, FCCP leads to similar readouts in C2C12 myotubes as dexamethasone does. On the contrary, resveratrol, a mitochondrial nutrient, efficiently reversed dexamethasone-induced mitochondrial dysfunction and muscle atrophy in both C2C12 myotubes and mice, by improving mitochondrial function and blocking AMPK/FOXO3 signaling. These results indicate that mitochondrial dysfunction acts as a central role in dexamethasone-induced skeletal muscle atrophy and that nutrients or drugs targeting mitochondria might be beneficial in preventing or curing muscle atrophy.