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首页> 外文期刊>Molecular and Cellular Biology >Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle
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Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle

机译：线粒体分裂促成骨骼肌线粒体功能障碍和胰岛素抵抗

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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 mitochondrial dysfunction and metabolic deterioration in skeletal muscle. First, we revealed that excess palmitate (PA), but not hyperglycemia, hyperinsulinemia, or elevated tumor necrosis factor 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.
机译：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，我们假设肥胖和过多的能量摄入会改变线粒体动力学的平衡，从而进一步加剧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），而不是高血糖症，高胰岛素血症或肿瘤坏死因子α升高，在分化的C2C12肌肉细胞中诱导了线粒体片段化，并增加了与线粒体相关的Drp1和Fis1。这种碎裂与氧化应激增加，线粒体去极化，ATP产生减少和胰岛素刺激的葡萄糖摄取减少有关。 Drp1的遗传和药理学抑制作用减弱了C2C12细胞中PA诱导的线粒体片段化，线粒体去极化和胰岛素抵抗。此外，我们发现患有遗传性肥胖的小鼠和饮食性肥胖的小鼠的骨骼肌中线粒体越来越小，线粒体分裂机制增加。线粒体裂变的抑制改善了肥胖小鼠的肌肉胰岛素信号传导和全身胰岛素敏感性。我们的发现表明，线粒体异常分裂与骨骼肌线粒体功能障碍和胰岛素抵抗有因果关系。因此，在肥胖和2型糖尿病中，线粒体动力学的破坏可能是肌肉胰岛素抵抗的发病机制的基础。

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