Sudevan, Surabhi et al. (2019) International Worm Meeting "Ca2+ overload due to mitochondrial dysfunction causes muscle ECM degradation."

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

[International Worm Meeting, 2019]

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 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, and calcium-dependent 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 downregulation rescued the muscle damage. In our previous publication, we could see that heat stress leads to cytoplasmic calcium overload and mitochondrial fragmentation, and finally induced similar muscle structural damage (Momma K. et al 2017). These results suggest 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, and would like to propose MMP and Furin inhibitors as promising candidates for drugs against muscle wasting conditions characterized by mitochondrial dysfunction, including DMD but also heatstroke, ageing and disuse/ bedrest. Surabhi S. et al., Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans. FASEB J 2019 in press. Monnma K. et al., Heat-Induced Calcium Leakage Causes Mitochondrial Damage in Caenorhabditis elegans Body-Wall Muscles. Genetics 2017, 206: 1985-1994.

Sudevan S et al. (2019) FASEB J "Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans."

Szewczyk NJ, Kubota Y, Takiura M, Ellwood RA, Sudevan S, Etheridge T, Cooke M, Higashitani N, Higashitani A

[FASEB J, 2019]

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 <i>Caenorhabditis elegans</i>. 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 <i>C. elegans</i> 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 <i>C. elegans</i>.