Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling
Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling
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DOI：
10.1210/en.2006-0251
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发表时间：
2006-09-01
期刊：
影响因子：
4.8
通讯作者：
Mitch, William E.
中科院分区：
文献类型：
--
作者：
Wang, Xiaonan;Hu, Zhaoyong;Mitch, William E.
诸如酸中毒、尿毒症和脓毒症等病症的特征在于胰岛素抵抗和肌肉萎缩，但与这些病症相关的胰岛素抵抗是否导致肌肉萎缩尚不清楚。我们在血糖升高的db/db小鼠中研究了这个问题，尽管血浆胰岛素水平很高。与同窝对照组小鼠相比，db/db小鼠各部位肌肉的重量和肌肉的横截面积均较小。在db/db小鼠的肌肉中，蛋白质降解和主要蛋白水解系统caspase-3和蛋白酶体的活性增加。我们检查了可以激活肌肉蛋白水解的信号，发现磷脂酰肌醇3激酶（PI 3 K）活性和磷酸化Akt的低值与胰岛素受体底物-1的丝氨酸307的磷酸化有关。为了评估循环胰岛素和葡萄糖的变化如何影响肌肉蛋白，我们用罗格列酮治疗db/db小鼠。罗格列酮改善胰岛素抵抗指数和PI 3 K/Akt信号传导异常，降低caspase-3和肌肉中蛋白酶体的活性，从而抑制蛋白水解。蛋白水解的潜在机制包括糖皮质激素产生增加、循环脂联素减少和叉头转录因子的磷酸化，这与E3泛素结合酶atrogin 1/MAFbx和MuRF 1的表达增加有关。罗格列酮也纠正了这些异常。因此，胰岛素抵抗通过涉及抑制PI 3 K/Akt信号传导导致半胱天冬酶-3活化和泛素-蛋白酶体蛋白水解途径导致肌肉蛋白降解的机制引起肌肉萎缩。
Conditions such as acidosis, uremia, and sepsis are characterized by insulin resistance and muscle wasting, but whether the insulin resistance associated with these disorders contributes to muscle atrophy is unclear. We examined this question in db/db mice with increased blood glucose despite high levels of plasma insulin. Compared with control littermate mice, the weights of different muscles in db/db mice and the cross-sectional areas of muscles were smaller. In muscle of db/db mice, protein degradation and activities of the major proteolytic systems, caspase-3 and the proteasome, were increased. We examined signals that could activate muscle proteolysis and found low values of both phosphatidylinositol 3 kinase (PI3K) activity and phosphorylated Akt that were related to phosphorylation of serine 307 of insulin receptor substrate-1. To assess how changes in circulating insulin and glucose affect muscle protein, we treated db/db mice with rosiglitazone. Rosiglitazone improved indices of insulin resistance and abnormalities in PI3K/Akt signaling and decreased activities of caspase-3 and the proteasome in muscle leading to suppression of proteolysis. Underlying mechanisms of proteolysis include increased glucocorticoid production, decreased circulating adiponectin, and phosphorylation of the forkhead transcription factor associated with increased expression of the E3 ubiquitin-conjugating enzymes atrogin1/MAFbx and MuRF1. These abnormalities were also corrected by rosiglitazone. Thus, insulin resistance causes muscle wasting by mechanisms that involve suppression of PI3K/Akt signaling leading to activation of caspase-3 and the ubiquitin-proteasome proteolytic pathway causing muscle protein degradation.