Renal Division, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
Int J Biochem Cell Biol. 2013 Oct;45(10):2230-8. doi: 10.1016/j.biocel.2013.06.027. Epub 2013 Jul 16.
Muscle atrophy is a frequent complication of chronic kidney disease (CKD) and is associated with increased morbidity and mortality. The processes causing loss of muscle mass are also present in several catabolic conditions. Understanding the pathogenesis of CKD-induced muscle loss could lead to therapeutic interventions that prevent muscle wasting in CKD and potentially, other catabolic conditions.
Insulin or IGF-1 resistance caused by CKD, acidosis, inflammation, glucocorticoids or cancer causes defects in insulin-stimulated intracellular signaling that suppresses IRS-1 activity leading to decreased phosphorylation of Akt (p-Akt). A low p-Akt activates caspase-3 which provides muscle proteins substrates of the ubiquitin-proteasome system (UPS). A low p-Akt also leads to decreased phosphorylation of forkhead transcription factors which enter the nucleus to stimulate the expression of atrogin-1/MAFbx and MuRF1, E3 ubiquitin ligases that can be associated with proteolysis of muscle cells by the UPS. Caspase-3 also stimulates proteasome-dependent proteolysis in muscle.
In CKD, diabetes, inflammatory conditions or in response to acidosis or excess glucocorticoids, insulin resistance develops, initiating reduced IRS-1/PI3K/Akt signaling. In CKD, this reduces p-Akt which stimulates muscle proteolysis by activating caspase-3 and the UPS. Second, caspase-3 cleaves actomyosin yielding substrates for the UPS and increased proteasome-mediated proteolysis. Third, p-Akt down-regulation suppresses myogenesis in CKD. Fourth, exercise in CKD stimulates insulin/IGF-1 signaling to reduce muscle atrophy. Lastly, there is evidence that microRNAs influence insulin signaling providing a potential opportunity to design therapeutic interventions. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.
肌肉萎缩是慢性肾脏病（CKD）的常见并发症，与发病率和死亡率的增加有关。导致肌肉质量损失的过程也存在于几种分解代谢状态中。了解 CKD 引起的肌肉丢失的发病机制可能导致治疗干预措施，以防止 CKD 中的肌肉浪费，并可能防止其他分解代谢状态中的肌肉浪费。
CKD、酸中毒、炎症、糖皮质激素或癌症引起的胰岛素或 IGF-1 抵抗导致胰岛素刺激的细胞内信号转导缺陷，抑制 IRS-1 活性，导致 Akt（p-Akt）磷酸化减少。低 p-Akt 激活半胱天冬酶-3，为泛素-蛋白酶体系统（UPS）提供肌肉蛋白底物。低 p-Akt 还导致叉头转录因子的磷酸化减少，这些转录因子进入细胞核刺激肌萎缩蛋白 1/MAFbx 和 MuRF1 的表达，E3 泛素连接酶可与 UPS 相关的肌肉细胞蛋白水解有关。半胱天冬酶-3还刺激肌肉中的蛋白酶体依赖性蛋白水解。
在 CKD、糖尿病、炎症状态或对酸中毒或糖皮质激素过量的反应中，会发生胰岛素抵抗，从而启动 IRS-1/PI3K/Akt 信号转导减少。在 CKD 中，这会降低 p-Akt，通过激活半胱天冬酶-3 和 UPS 来刺激肌肉蛋白水解。其次，半胱天冬酶-3 切割肌球蛋白和肌动蛋白，产生 UPS 的底物并增加蛋白酶体介导的蛋白水解。第三，p-Akt 下调抑制 CKD 中的成肌作用。第四，CKD 中的运动刺激胰岛素/IGF-1 信号转导以减少肌肉萎缩。最后，有证据表明 microRNAs 影响胰岛素信号转导，为设计治疗干预措施提供了潜在机会。本文是主题为“肌肉减少症的分子基础”的定向问题的一部分。
