Key result
Redox modulators or β-actin overexpression prevent eccentric contraction-induced force loss in knockout mice.
Why the study?
The mechanisms underlying eccentric contraction-induced force loss in dystrophin-deficient mdx skeletal muscle remain incompletely understood.
Does treatment with redox modulators or transgenic β-actin overexpression prevent eccentric contraction-induced force loss in ms-Actb KO mice?
Does treatment with redox modulators or transgenic β-actin overexpression prevent eccentric contraction-induced force loss in ms-Actb KO mice?
Oxidative stress and altered redox metabolism are critical regulators of eccentric contraction-induced force loss in both dystrophin-deficient and cytoplasmic β-actin-deficient models of myopathy.
Provides mechanistic insights into dystrophin-actin interactions in a murine model; leaves open whether targeting.
Background Eccentric contraction (ECC)-induced force loss is one of the most robust and reproducible phenotypes of the dystrophin-deficient mdx mouse, which is the most widely studied model of Duchenne muscular dystrophy. Despite its utility as a quantitative assessment of therapeutic efficacy in preclinical trials, the mechanism of ECC force loss in mdx skeletal muscle remains incompletely understood. We have previously shown that dystrophin directly interacts with non-muscle cytoplasmic actin isoforms in structures called “costameres” and that oxidative stress and altered redox metabolism contribute to ECC force loss in mdx muscle. Methods Key methods include physiological measurement of skeletal muscle isometric and eccentric force (in vitro) and torque (in vivo), DCF fluorescence, and histopathological and biochemical assessment of skeletal muscle. Results Here we demonstrate that extensor digitorum longus (EDL) muscles from muscle-specific, cytoplasmic β-actin knockout (ms-Actb KO) mice also present with significant ECC force loss, but the phenotype progresses more slowly and is of lower magnitude compared to mdx EDL muscles. We further demonstrate that muscle-specific transgenic overexpression of cytoplasmic β-actin protects ms-Actb KO muscles from ECC force loss. Consistent with our previous results in mdx mice, treatment of ms-Actb KO EDL muscles with the redox modulators N-acetylcysteine or the H2S donor sodium hydrogen sulfide prevents ECC force loss to a similar extent as transgenic cytoplasmic β-actin replacement. Different from mdx, however, ms-Actb KO ECC force loss occurs in the absence of a concomitant increase in ECC-induced reactive oxygen species production. Conclusions Our results implicate oxidative stress and altered redox metabolism as critical regulators of ECC force loss in two independent models of myopathy. Together, the data presented here enhance the understanding of ECC force loss in both dystrophin-deficient and cytoplasmic β-actin-deficient forms of myopathy, specifically expanding on a unifying, redox-based mechanism of ECC force loss to include a non-dystrophin-deficient model of myopathy.
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Fallon et al. (2026) studied Myopathy (mouse model). Redox modulators (N-acetylcysteine or sodium hydrogen sulfide) or transgenic cytoplasmic β-actin overexpression vs. Untreated ms-Actb KO mice was evaluated on Eccentric contraction (ECC)-induced force loss. In a muscle-specific cytoplasmic β-actin knockout mouse model, treatment with redox modulators or transgenic β-actin overexpression prevented eccentric contraction-induced force loss.
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