CKD Stimulates Muscle Protein Loss Via Rho-associated Protein Kinase 1 Activation
CKD Stimulates Muscle Protein Loss Via Rho-associated Protein Kinase 1 Activation
复制标题
CKD 通过 Rho 相关蛋白激酶 1 激活刺激肌肉蛋白损失
DOI：
10.1681/asn.2014121208
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发表时间：
2016-02-01
影响因子：
13.6
通讯作者：
Hu, Zhaoyong
中科院分区：
文献类型：
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作者：
Peng, Hui;Cao, Jin;Hu, Zhaoyong
在 CKD 患者中，肌肉萎缩很常见，并且与发病率和死亡率相关。导致肌肉蛋白损失的机制包括胰岛素抵抗，胰岛素抵抗会抑制 Akt 活性，从而通过泛素-蛋白酶体系统刺激蛋白质降解。然而，控制 CKD 诱导的肌肉 Akt 活性抑制的具体因素仍不清楚。在患有 CKD 的小鼠中，肌肉中 Akt 活性的降低超过了上游胰岛素受体底物 1 相关磷脂酰肌醇 3-激酶活性的降低，表明 CKD 激活了抑制 Akt 的其他途径。此外，CKD 诱导的这些小鼠肌肉中 caspase-3 活性的增加。在 C2C12 肌肉细胞中，激活的 caspase-3 会裂解并激活 Rho 相关蛋白激酶 1 (ROCK1)，从而增强磷酸酶和张力蛋白同源物 (PTEN) 的活性并降低 Akt 活性。值得注意的是，ROCK1 的组成型激活还导致体外 caspase-3 活性增加。在整体 ROCK1 敲除或肌肉特异性 PTEN 敲除的小鼠中，CKD 相关的肌肉蛋白水解作用减弱。这些结果表明，CKD 中以及其他分解代谢条件下的 ROCK1 激活可以通过负反馈循环促进肌肉蛋白的损失。
In patients with CKD, muscle wasting is common and is associated with morbidity and mortality. Mechanisms leading to loss of muscle proteins include insulin resistance, which suppresses Akt activity and thus stimulates protein degradation via the ubiquitin-proteasome system. However, the specific factors controlling CKD-induced suppression of Akt activity in muscle remain undefined. In mice with CKD, the reduction in Akt activity in muscle exceeded the decrease in upstream insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity, suggesting that CKD activates other pathways that suppress Akt. Furthermore, a CKD-induced increase uncovered caspase-3 activity in muscle in these mice. In C2C12 muscle cells, activated caspase-3 cleaves and activates Rho-associated protein kinase 1 (ROCK1), which enhances the activity of phosphatase and tensin homolog (PTEN) and reduces Akt activity. Notably, constitutive activation of ROCK1 also led to increased caspase-3 activity in vitro. In mice with either global ROCK1 knockout or muscle-specific PTEN knockout, CKD-associated muscle proteolysis was blunted. These results suggest ROCK1 activation in CKD and perhaps in other catabolic conditions can promote loss of muscle protein via a negative feedback loop.