Evidence for a Reversible, Redox-Mediated Component to Eccentric Contraction-Induced Force Loss in Dystrophin-Deficient Skeletal Muscle

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Evidence for a Reversible, Redox-Mediated Component to Eccentric Contraction-Induced Force Loss in Dystrophin-Deficient Skeletal Muscle

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2018-04

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Duchenne muscular dystrophy (DMD) is one of the most common and severe forms of muscular dystrophy. To better understand eccentric contraction-induced force loss in dystrophic muscle, we used iTRAQ proteomics to identify proteins that were differentially expressed in mdx mice overexpressing nonmuscle γcyto-actin (mdx/Actg1-TG), which we have previously shown to significantly protect mdx muscle against force loss. We identified peroxiredoxin-2 (PrxII) as significantly decreased in mdx muscle compared to WT but restored to WT levels in mdx/Actg1-TG muscle. We show that increased sarcolemmal NADPH Oxidase 2 (NOX2)-dependent ROS production contributes to eccentric contraction-induced force loss while causing hyperoxidation and subsequent proteasomal degradation of PrxII in mdx muscle. Interestingly, ablation of PrxII exacerbated force loss in mdx muscle, while overexpression of PrxII led to a dose-dependent protection of force loss. We also establish the contribution of myoglobin to force loss in mdx muscle through the production of hydroxyl radicals. Finally, we demonstrate that oxidation-sensitive cysteine 272 unique to γcyto- and βcyto-actins is required to protect mdx muscle from force loss through inhibition of NOX2-dependent ROS production. Together, the data presented in this dissertation suggest that eccentric contractions may induce a rapidly reversible, redox-mediated inhibition of contractility, thus acting as a “circuit breaker” to protect mdx muscle from more disastrous structural damage during subsequent high force contractions.

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University of Minnesota Ph.D. dissertation.April 2018. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: James Ervasti. 1 computer file (PDF); vii, 135 pages.

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Olthoff, John. (2018). Evidence for a Reversible, Redox-Mediated Component to Eccentric Contraction-Induced Force Loss in Dystrophin-Deficient Skeletal Muscle. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/203593.

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