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.
Bibliographical noteFunding Information:
The iTRAQ proteomic screen was performed at the University of Minnesota Center for Mass Spectrometry and Proteomics, with LeeAnn Higgins and Todd Markowski providing much appreciated assistance in sample preparation and data analysis. The mdx/ Coco transgenic mice were kindly provided by Dr. Kay Davies of the Medical Research Council, along with Dr. Nigel Laing and Dr. Kristen Nowak of the University of Western Australia. Rederivation of the PrxII–/– mouse line was performed at the University of Minnesota Mouse Genetics Laboratory. Pronuclear injection and embryo implantation of transgenic mice were accomplished at The Scripps Research Institute Murine Genetics Core. Fascin-1 cDNA was a kind gift from Dr. Steven Almo of the Albert Einstein College of Medicine. We also thank Nigel Laing of the University of Western Australia for helpful comments on the manuscript. This study was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases grants to J.M.E. (R01AR049899) and G.G.R. (R01AR061370). J.T.O., J.J.B., and K.A.B. were supported by the National Institutes of Health Training Program in Muscle Research (T32AR007612). J.T.O. was further supported by the National Institute of Aging Training Program for Functional Proteomics of Aging (T32AG029796). J.J.B. was also supported by a University of Minnesota Doctoral Dissertation Fellowship.