PGC-1α integrates insulin signaling, mitochondrial regulation, and bioenergetic function in skeletal muscle
PGC-1α integrates insulin signaling, mitochondrial regulation, and bioenergetic function in skeletal muscle
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DOI：
10.1074/jbc.m800842200
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发表时间：
2008-08-15
影响因子：
4.8
通讯作者：
Sack, Michael N.
中科院分区：
文献类型：
--
作者：
Pagel-Langenickel, Ines;Bao, Jianjun;Sack, Michael N.
胰岛素抵抗骨骼肌线粒体功能障碍的病理生理学特征尚不完全。为了进一步阐明这一点，我们研究了胰岛素信号传导，线粒体调节和功能之间的相互作用，在C2 C12肌管和骨骼肌。在肌管中，升高的胰岛素和葡萄糖破坏胰岛素信号传导、线粒体生物发生和线粒体生物能量学。胰岛素增敏噻唑烷二酮吡格列酮恢复这些扰动与诱导线粒体生物合成调节剂PGC-1 α平行。PGC-1 α的过表达拯救胰岛素信号传导和线粒体生物能量学，并且其沉默一致地破坏胰岛素信号传导和线粒体生物能量学。在原代骨骼肌成肌细胞中，吡格列酮还上调PGC-1 α表达，并恢复胰岛素抵抗线粒体生物能谱。同时，吡格列酮上调db/db小鼠骨骼肌中的PGC-1 α。有趣的是，C2 C12肌管中胰岛素受体的小干扰RNA敲低下调PGC-1 α并减弱线粒体生物能量学。一致地，在胰岛素受体敲除小鼠来源的骨骼肌成肌细胞中，线粒体生物能量学是钝化的。总之，这些数据表明，升高的葡萄糖和胰岛素损害和吡格列酮恢复骨骼肌管胰岛素信号传导，线粒体调节和生物能量学。吡格列酮部分通过诱导PGC-1 α发挥作用。此外，PGC-1 α被鉴定为整合骨骼肌中胰岛素信号传导和线粒体稳态的双向调节环节。
The pathophysiology underlying mitochondrial dysfunction in insulin-resistant skeletal muscle is incompletely characterized. To further delineate this we investigated the interaction between insulin signaling, mitochondrial regulation, and function in C2C12 myotubes and in skeletal muscle. In myotubes elevated insulin and glucose disrupt insulin signaling, mitochondrial biogenesis, and mitochondrial bioenergetics. The insulin-sensitizing thiazolidinedione pioglitazone restores these perturbations in parallel with induction of the mitochondrial biogenesis regulator PGC-1 alpha. Overexpression of PGC-1 alpha rescues insulin signaling and mitochondrial bioenergetics, and its silencing concordantly disrupts insulin signaling and mitochondrial bioenergetics. In primary skeletal myoblasts pioglitazone also up-regulates PGC-1 alpha expression and restores the insulin-resistant mitochondrial bioenergetic profile. In parallel, pioglitazone upregulates PGC-1 alpha in db/db mouse skeletal muscle. Interestingly, the small interfering RNA knockdown of the insulin receptor in C2C12 myotubes down-regulates PGC-1 alpha and attenuates mitochondrial bioenergetics. Concordantly, mitochondrial bioenergetics are blunted in insulin receptor knock-out mouse-derived skeletal myoblasts. Taken together these data demonstrate that elevated glucose and insulin impairs and pioglitazone restores skeletal myotube insulin signaling, mitochondrial regulation, and bioenergetics. Pioglitazone functions in part via the induction of PGC-1 alpha. Moreover, PGC-1 alpha is identified as a bidirectional regulatory link integrating insulin-signaling and mitochondrial homeostasis in skeletal muscle.