Atrogin-1 promotes muscle homeostasis by regulating levels of endoplasmic reticulum chaperone BiP.

Autor:	Ruparelia AA; Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.; Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, and.; Centre for Muscle Research, Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia., Montandon M; Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia., Merriner J; Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia., Huang C; Monash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia., Wong SFL; Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia., Sonntag C; Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia., Hardee JP; Centre for Muscle Research, Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia., Lynch GS; Centre for Muscle Research, Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia., Miles LB; Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia., Siegel A; Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia., Hall TE; Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia., Schittenhelm RB; Monash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia., Currie PD; Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.; EMBL Australia, Victorian Node, Monash University, Clayton, Victoria, Australia.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2024 Mar 26; Vol. 9 (8). Date of Electronic Publication: 2024 Mar 26.
DOI:	10.1172/jci.insight.167578
Abstrakt:	Skeletal muscle wasting results from numerous pathological conditions affecting 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 of 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 resulted in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fiber integrity. We further implicated a disruption in atrogin-1-mediated BiP regulation in the pathogenesis of Duchenne muscular dystrophy. We revealed that BiP was not only upregulated in Duchenne muscular dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorated pathology in a zebrafish model of Duchenne muscular dystrophy. Collectively, our data implicate atrogin-1 and BiP in the pathogenesis of Duchenne muscular dystrophy and highlight atrogin-1's essential role in maintaining muscle homeostasis.
Databáze:	MEDLINE
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