Molecular signaling pathways regulating muscle proteolysis during atrophy
Molecular signaling pathways regulating muscle proteolysis during atrophy
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DOI：
10.1097/01.mco.0000165005.01331.45
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发表时间：
2005-05-01
影响因子：
3.1
通讯作者：
Price, SR
中科院分区：
文献类型：
--
作者：
Franch, HA;Price, SR
虽然各种不同的刺激诱导肌肉萎缩，但在细胞内反应中有惊人的相似性。一个突出的反应是由于泛素-蛋白酶体途径的刺激而导致肌肉蛋白水解的增加。了解调节肌肉质量的细胞内信号通路将有助于了解细胞反应的协调。本文将对肌肉萎缩过程中调节蛋白质水解的分子信号通路的最新发现进行综述。几种肌肉特异性E3泛素连接酶的表达在引起肌肉萎缩的情况下持续增加。胰岛素和胰岛素样生长因子-1通过磷酸肌肽3-激酶/AKT通路抑制这两种酶MuRF1和MAFbx/atrogin-1的表达。确定肌肉特异性E3连接酶靶标的努力正在产生有趣的信息。胰岛素和胰岛素样生长因子-1也可以通过抑制caspase-3来减轻消瘦，caspase-3可以裂解肌动蛋白，促进其被泛素-蛋白酶体系统破坏。其他参与肌肉质量调节的信号系统包括核因子κ B通路。肌肉质量的维持需要分解代谢因子和合成代谢因子之间的微妙平衡。这些信号反向调节几个关键调控通路的活性，包括磷酸肌醇-3激酶/AKT和核因子κ B系统，它们控制泛素-蛋白酶体蛋白水解途径活性组分的转录，caspase-3的活性，以及其他蛋白水解功能。当胰岛素或胰岛素样生长因子-1水平不足或炎症细胞因子产生增加时，肌肉萎缩随之而来。
Purpose of review Although a variety of diverse stimuli induce muscle atrophy, there is a surprising number of similarities in the intracellular responses. One prominent response is an increase in muscle proteolysis resulting from stimulation of the ubiquitin-proteasome pathway. Understanding the intracellular signaling pathways that regulate muscle mass should offer insights into the coordination of cellular responses. This review will discuss recent findings on the molecular signaling pathways regulating proteolysis during muscle atrophy.Recent findings The expression of several muscle-specific E3 ubiquitin ligases is consistently increased in conditions causing muscle atrophy. Insulin and insulin-like growth factor-1 act through the phosphoinositide 3-kinase/AKT pathway to suppress the expression of two of these enzymes, MuRF1 and MAFbx/atrogin-1. Efforts to identify targets of the muscle-specific E3 ligases are yielding interesting information. Insulin and insulin-like growth factor-1 also attenuate wasting by inhibiting caspase-3, which cleaves actin to facilitate its destruction by the ubiqutin-proteasome system. Other signaling systems involved in the regulation of muscle mass include the nuclear factor kappa B pathway.Summary The maintenance of muscle mass requires a delicate balance between catabolic factors and anabolic factors. These signals inversely modulate the activity of several key regulatory pathways including the phosphoinositide-3 kinase/AKT and nuclear factor kappa B systems, which control the transcription of components of the ubiquitin-proteasome proteolytic pathway activity, the activity of caspase-3, and perhaps other proteolytic functions. When levels of insulin or insulin-like growth factor-1 are insufficient or inflammatory cytokine production is increased, muscle atrophy ensues.