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Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation
Biomolecules ( IF 4.8 ) Pub Date : 2021-09-08 , DOI: 10.3390/biom11091327
Stefanie Haberecht-Müller 1 , Elke Krüger 1 , Jens Fielitz 2, 3
Affiliation  

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.

中文翻译:

失控:炎症期间泛素蛋白酶体系统在骨骼肌中的作用

大多数重症重症监护病房 (ICU) 患有严重脓毒症的患者会出现 ICU 获得性虚弱 (ICUAW),其特征是肌肉质量减少、肌纤维尺寸减小和肌肉力量下降,从而导致持续的身体损伤。这种表型是由蛋白质稳态失调引起的,蛋白质降解增加和蛋白质合成减少,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,在不同的肌肉萎缩情况(例如炎症)中被激活。UPS 介导的蛋白质降解的特异性由 E3 泛素连接酶保证,例如 atrogin-1 和 MuRF1,它们靶向结构和收缩蛋白,参与能量代谢的蛋白质和 UPS 依赖性降解的转录因子。尽管 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已广为人知,但蛋白酶体对炎症期间肌肉萎缩的贡献仍然难以捉摸。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,这在多大程度上会导致肌肉萎缩,以及这是否会改变特定肌肉蛋白的靶向性并没有得到很好的描述。本综述总结了主要促炎细胞因子和急性期反应蛋白的功能及其在炎症诱导的肌肉萎缩中的信号通路,重点关注脓毒症期间 UPS 介导的肌肉蛋白质降解。将报告主要 E3 泛素连接酶在肌肉萎缩中的调节和靶特异性及其对肌原纤维蛋白的作用方式。将描述标准蛋白酶体和免疫蛋白酶体在炎症诱导的肌肉萎缩中的功能,并将讨论蛋白酶体抑制剂作为治疗策略的作用。
更新日期:2021-09-08
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