Mitch William E, Hu Zhaoyong, Lee Seoung Woo, Du Jie
Department of Medicine, University of Texas Medical Branch, Galveston, TX, USA.
J Ren Nutr. 2005 Jan;15(1):23-7. doi: 10.1053/j.jrn.2004.09.025.
Loss of protein and lean body mass occurs commonly in patients with chronic kidney disease (CKD). CKD or conditions associated with CKD will stimulate muscle loss, but the cellular mechanisms by which these conditions cause muscle atrophy are largely undefined. In animal models of uremia and other catabolic conditions or in peritoneal dialysis patients, there is evidence that the ubiquitin-proteasome proteolytic system is activated to degrade actomyosin and myofibrillar proteins in muscle. Before the ubiquitin system can degrade muscle proteins, however, an initial cleavage of actomyosin and myofibrils must occur. Caspase-3 performs this initial cleavage of actomyosin and leaves a footprint of its activity, accumulation of a 14-kDa actin fragment in muscle. A critical step in stimulating the ubiquitin-proteasome system in muscle was recently discovered, the activation of a specific E3 ubiquitin-conjugating enzyme, atrogin-1. Both caspase-3 and the ubiquitin system, including atrogin-1, are activated when insulin signaling is impaired, and specifically when phosphatidylinositol 3 kinase activity is suppressed. Strategies that prevent a decrease in phosphatidylinositol 3 kinase activity or inhibit caspase-3 activity could lead to treatments that prevent muscle wasting in CKD patients.
蛋白质和瘦体重的流失在慢性肾脏病（CKD）患者中很常见。CKD或与CKD相关的病症会刺激肌肉流失，但这些病症导致肌肉萎缩的细胞机制在很大程度上尚不清楚。在尿毒症和其他分解代谢病症的动物模型中，或在腹膜透析患者中，有证据表明泛素 - 蛋白酶体蛋白水解系统被激活，以降解肌肉中的肌动球蛋白和肌原纤维蛋白。然而，在泛素系统能够降解肌肉蛋白之前，肌动球蛋白和肌原纤维必须先进行初步切割。半胱天冬酶 - 3执行肌动球蛋白的这种初步切割，并留下其活性的痕迹，即肌肉中14 kDa肌动蛋白片段的积累。最近发现了刺激肌肉中泛素 - 蛋白酶体系统的关键步骤，即一种特定的E3泛素连接酶atrogin - 1的激活。当胰岛素信号受损时，特别是当磷脂酰肌醇3激酶活性受到抑制时，半胱天冬酶 - 3和包括atrogin - 1在内的泛素系统都会被激活。防止磷脂酰肌醇3激酶活性降低或抑制半胱天冬酶 - 3活性的策略可能会带来预防CKD患者肌肉消瘦的治疗方法。
