Journal
FASEB JOURNAL
Volume 33, Issue 8, Pages 9540-9550Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201802298R
Keywords
Antimycin A; collagen; Furin; DMD; MMP
Categories
Funding
- U.S. National Institutes of Health (NIH) Office of Research Infrastructure Program [P40OD010440]
- Ministry of Education, Culture, Sports, Science, and Technology (MEXT) [15H05937, 15K21745]
- Cross-Ministerial Strategic Innovation Promotion Program [14537491]
- Advanced Research and Development Programs for Medical Innovation (AMED-CREST) [16814305]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/N015894/1, BB/P025781/1]
- UK Space Agency
- Science and Technology Facilities Council [ST/R005737/1]
- Otsuka Toshimi Foundation
- Tohoku University President scholarship
- Japan Student Services Organization
- BBSRC [BB/P025781/1, BB/N015894/1] Funding Source: UKRI
- STFC [2116193] Funding Source: UKRI
- Grants-in-Aid for Scientific Research [15H05937] Funding Source: KAKEN
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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.-Sudevan, S., Takiura, M., Kubota, Y., Higashitani, N., Cooke, M., Ellwood, R. A., Etheridge, T., Szewczyk, N. J., Higashitani, A. Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans.
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