Olthoff, John T.Lindsay, AngusAbo-Zahrah, ReemBaltgalvis, Kristen A.Patrinostro, XiaobaiBelanto, Joseph J.Yu, Dae-YeulPerrin, Benjamin J.Garry, Daniel J.Rodney, George G.Lowe, Dawn A.Ervasti, James M.2019-05-232019-05-232018-11-30Olthoff, J. T., Lindsay, A., Abo-Zahrah, R., Baltgalvis, K. A., Patrinostro, X., Belanto, J. J., … Ervasti, J. M. (2018). Loss of peroxiredoxin-2 exacerbates eccentric contraction-induced force loss in dystrophin-deficient muscle. Nature communications, 9(1), 5104. doi:10.1038/s41467-018-07639-3https://hdl.handle.net/1805/19445Force 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.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesDystrophinImmunoblottingImmunoprecipitationMuscle contractionPeroxiredoxinsLoss of peroxiredoxin-2 exacerbates eccentric contraction-induced force loss in dystrophin-deficient muscleArticle