Mitochondrial dysfunction causes Ca2+ overload and ECM degradation–mediated muscle damage in C. elegans

Sudevan, Surabhi; Takiura, Mai; Kubota, Yukihiko; Higashitani, Nahoko; Cooke, Michael; Ellwood, Rebecca A.; Etheridge, Timothy; Szewczyk, Nathaniel J.; Higashitani, Atsushi

Abstract

Mitochondrial dysfunction impairs muscle health and causes subsequent muscle wasting. This study explores the role of mitochondrial dysfunction as an intramuscular signal for the extracellular matrix (ECM)–based proteolysis and, consequentially, muscle cell dystrophy. We found that inhibition of the mitochondrial electron transport chain causes paralysis as well as muscle structural damage in the nematode Caenorhabditis elegans. This was associated with a significant decline in collagen content. Both paralysis and muscle damage could be rescued with collagen IV overexpression, matrix metalloproteinase (MMP), and Furin inhibitors in Antimycin A–treated animal as well as in the C. elegans Duchenne muscular dystrophy model. Additionally, muscle cytosolic calcium increased in the Antimycin A–treated worms, and its down-regulation rescued the muscle damage, suggesting that calcium overload acts as one of the early triggers and activates Furin and MMPs for collagen degradation. In conclusion, we have established ECM degradation as an important pathway of muscle damage.

Citation

Sudevan, S., Takiura, M., Kubota, Y., Higashitani, N., Cooke, M., Ellwood, R. A., …Higashitani, A. (2019). Mitochondrial dysfunction causes Ca2+ overload and ECM degradation–mediated muscle damage in C. elegans. FASEB Journal, 33(8), 9540-9550. https://doi.org/10.1096/fj.201802298r

• Journal Article Type: Article
• Acceptance Date: Apr 29, 2019
• Online Publication Date: Jun 4, 2019
• Publication Date: 2019-08
• Deposit Date: Jun 16, 2019
• Publicly Available Date: Jun 17, 2019
• Journal: The FASEB Journal
• Print ISSN: 0892-6638
• Electronic ISSN: 1530-6860
• Publisher: Federation of American Society of Experimental Biology (FASEB)
• Peer Reviewed: Peer Reviewed
• Volume: 33
• Issue: 8
• Pages: 9540-9550
• DOI: https://doi.org/10.1096/fj.201802298r
• Keywords: Biotechnology; Genetics; Biochemistry; Molecular Biology
• Public URL: https://nottingham-repository.worktribe.com/output/2192818
• Publisher URL: https://www.fasebj.org/doi/10.1096/fj.201802298R
• Contract Date: Jun 16, 2019