Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation.
Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation.
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DOI：
10.3390/biom11091327
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发表时间：
2021-09-08
期刊：
影响因子：
5.5
通讯作者：
Fielitz J
中科院分区：
文献类型：
--
作者：
Haberecht-Müller S;Krüger E;Fielitz J
大多数重症监护室（ICU）严重脓毒症患者发生ICU获得性无力（ICUAW），其特征为肌肉质量损失、肌纤维尺寸减小和肌肉力量下降，导致持续的身体损害。这种表型是由于蛋白质稳态失调，蛋白质降解增加，蛋白质合成减少，最终导致肌肉结构蛋白减少。泛素蛋白酶体系统（UPS）是肌肉中主要的蛋白质降解系统，其在多种肌肉萎缩病症期间被激活，例如，炎症UPS介导的蛋白质降解的特异性由E3泛素连接酶（如atrogin-1和MuRF 1）确保，其靶向结构和收缩蛋白、参与能量代谢的蛋白质和用于UPS依赖性降解的转录因子。虽然E3泛素连接酶在炎症诱导的肌肉萎缩中的活性和功能的调节被很好地认识到，但是蛋白酶体在炎症期间肌肉萎缩中的贡献仍然是难以捉摸的。在炎症期间，描述了从标准蛋白酶体到免疫蛋白酶体的转变;然而，这在多大程度上导致肌肉萎缩以及这是否改变了特定肌肉蛋白的靶向，还没有很好地描述。本文综述了脓毒症时主要促炎细胞因子和急性时相反应蛋白及其信号通路在炎症诱导的肌肉萎缩中的作用，重点介绍了脓毒症时UPS介导的肌肉蛋白降解。主要的E3泛素连接酶在肌肉萎缩中的调节和靶向特异性及其对肌原纤维蛋白的作用模式将被报道。标准和免疫蛋白酶体在炎症引起的肌肉萎缩中的作用将被描述，蛋白酶体抑制剂作为治疗策略的效果将被讨论。
The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed.
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