杜氏肌营养不良
内质网
斑马鱼
泛素连接酶
下调和上调
细胞生物学
骨骼肌
蛋白质降解
生物
未折叠蛋白反应
泛素
肌营养不良
平衡
肌发生
肌肉萎缩
ITGA7型
发病机制
内分泌学
免疫学
生物化学
遗传学
基因
作者
Avnika A. Ruparelia,Margo Montandon,Jo Merriner,Cheng Huang,Siew Fen Lisa Wong,Carmen Sonntag,Justin P. Hardee,Gordon S. Lynch,Lee B. Miles,Ashley Siegel,Thomas Hall,Ralf B. Schittenhelm,Peter D. Currie
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2024-03-26
标识
DOI:10.1172/jci.insight.167578
摘要
Skeletal muscle wasting results from numerous pathological conditions impacting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined. Here, using zebrafish loss of function models combined with in vivo cell biology and proteomic approaches, we reveal a role of atrogin-1 in regulating the levels of the endoplasmic reticulum chaperone BiP. Loss of atrogin-1 results in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fibre integrity. We further implicate a disruption in atrogin-1 mediated BiP regulation in the pathogenesis of Duchenne muscular dystrophy. We reveal that BiP is not only upregulated in Duchenne muscular dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorates pathology in a zebrafish model of Duchenne muscular dystrophy. Collectively, our data implicates atrogin-1 and BiP in the pathogenesis of Duchenne muscular dystrophy, and highlights atrogin-1's essential role in maintaining muscle homeostasis.
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