Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle
Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle
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DOI：
10.1128/mcb.05603-11
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发表时间：
2012-01-01
影响因子：
5.3
通讯作者：
Tsai, Yau-Sheng
中科院分区：
文献类型：
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作者：
Jheng, Huei-Fen;Tsal, Pei-Jane;Tsai, Yau-Sheng
骨骼肌线粒体功能障碍与胰岛素抵抗和2型糖尿病的发生有关。考虑到线粒体动力学在线粒体和细胞功能中的重要性，我们假设肥胖和过量能量摄入改变了线粒体动力学的平衡，进一步导致线粒体功能障碍和骨骼肌代谢恶化。首先，我们发现过量的棕榈酸酯(PA)，而不是高血糖，高胰岛素血症，或升高的肿瘤坏死因子或α，在分化的C2C12肌肉细胞中诱导线粒体碎裂和增加线粒体相关的Drp1和Fis1。这种碎裂与氧化应激增加、线粒体去极化、三磷酸腺苷产生的丧失以及胰岛素刺激的葡萄糖摄取减少有关。基因和药物抑制均可减轻PA诱导的C2C12细胞线粒体断裂、线粒体去极化和胰岛素抵抗。此外，我们在遗传性肥胖和饮食诱导肥胖小鼠的骨骼肌中发现了更小、更短的线粒体，并增加了线粒体分裂机制。抑制线粒体分裂可改善肥胖小鼠肌肉胰岛素信号转导和全身胰岛素敏感性。我们的研究结果表明，线粒体分裂异常与骨骼肌线粒体功能障碍和胰岛素抵抗有关。因此，线粒体动力学的破坏可能是肥胖和2型糖尿病肌肉胰岛素抵抗的基础。
Mitochondrial dysfunction in skeletal muscle has been implicated in the development of insulin resistance and type 2 diabetes. Considering the importance of mitochondrial dynamics in mitochondrial and cellular functions, we hypothesized that obesity and excess energy intake shift the balance of mitochondrial dynamics, further contributing to mitochondria] dysfunction and metabolic deterioration in skeletal muscle. First, we revealed that excess palmitate (PA), but not hyperglycemia, hyperinsulinemia, or elevated tumor necrosis fact or alpha, induced mitochondrial fragmentation and increased mitochondrion-associated Drp1 and Fis1 in differentiated C2C12 muscle cells. This fragmentation was associated with increased oxidative stress, mitochondrial depolarization, loss of ATP production, and reduced insulin-stimulated glucose uptake. Both genetic and pharmacological inhibition of Drp1 attenuated PA-induced mitochondrial fragmentation, mitochondrial depolarization, and insulin resistance in C2C12 cells. Furthermore, we found smaller and shorter mitochondria and increased mitochondrial fission machinery in the skeletal muscle of mice with genetic obesity and those with diet-induced obesity. Inhibition of mitochondrial fission improved the muscle insulin signaling and systemic insulin sensitivity of obese mice. Our findings indicated that aberrant mitochondrial fission is causally associated with mitochondrial dysfunction and insulin resistance in skeletal muscle. Thus, disruption of mitochondrial dynamics may underlie the pathogenesis of muscle insulin resistance in obesity and type 2 diabetes.