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 and James M. Ervasti ()
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John T. Olthoff: University of Minnesota
Angus Lindsay: University of Minnesota
Reem Abo-Zahrah: Baylor College of Medicine
Kristen A. Baltgalvis: University of Minnesota
Xiaobai Patrinostro: University of Minnesota
Joseph J. Belanto: University of Minnesota
Dae-Yeul Yu: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Benjamin J. Perrin: Indiana University-Purdue University Indianapolis
Daniel J. Garry: University of Minnesota
George G. Rodney: Baylor College of Medicine
Dawn A. Lowe: University of Minnesota
James M. Ervasti: University of Minnesota

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07639-3

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