Loss of peroxiredoxin-2 exacerbates eccentric contraction-induced force loss in dystrophin-deficient muscle

John T. Olthoff, Angus Lindsay, Reem Abo-Zahrah, Kristen A. Baltgalvis, Xiaobai Patrinostro, Joseph J. Belanto, Dae Yeul Yu, Benjamin J. Perrin, Daniel J. Garry, George G. Rodney, Dawn A. Lowe, James M. Ervasti

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Abstract

Force loss in skeletal muscle exposed to eccentric contraction is often attributed to injury. We show that EDL muscles from dystrophin-deficient mdx mice recover 65% of lost force within 120 min of eccentric contraction and exhibit minimal force loss when the interval between contractions is increased from 3 to 30 min. A proteomic screen of mdx muscle identified an 80% reduction in the antioxidant peroxiredoxin-2, likely due to proteolytic degradation following hyperoxidation by NADPH Oxidase 2. Eccentric contraction-induced force loss in mdx muscle was exacerbated by peroxiredoxin-2 ablation, and improved by peroxiredoxin-2 overexpression or myoglobin knockout. Finally, overexpression of γcyto- or βcyto-actin protects mdx muscle from eccentric contraction-induced force loss by blocking NADPH Oxidase 2 through a mechanism dependent on cysteine 272 unique to cytoplasmic actins. Our data suggest that eccentric contraction-induced force loss may function as an adaptive circuit breaker that protects mdx muscle from injurious contractions.

Original languageEnglish (US)
Article number5104
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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Olthoff, J. T., Lindsay, A., Abo-Zahrah, R., Baltgalvis, K. A., Patrinostro, X., Belanto, J. J., Yu, D. Y., Perrin, B. J., Garry, D. J., Rodney, G. G., Lowe, D. A., & Ervasti, J. M. (2018). Loss of peroxiredoxin-2 exacerbates eccentric contraction-induced force loss in dystrophin-deficient muscle. Nature communications, 9(1), [5104]. https://doi.org/10.1038/s41467-018-07639-3