Impaired hydrogen sulfide biosynthesis underlies eccentric contraction–induced force loss in dystrophin-deficient skeletal muscle
W. Michael Southern, … , George G. Rodney, James M. Ervasti
W. Michael Southern, … , George G. Rodney, James M. Ervasti
Published January 14, 2025
Citation Information: J Clin Invest. 2025;135(5):e176942. https://doi.org/10.1172/JCI176942.
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Research Article Metabolism Muscle biology

Impaired hydrogen sulfide biosynthesis underlies eccentric contraction–induced force loss in dystrophin-deficient skeletal muscle

Abstract

Eccentric contraction–induced (ECC-induced) force loss is a hallmark of murine dystrophin-deficient (mdx) skeletal muscle that is used to assess efficacy of potential therapies for Duchenne muscular dystrophy. While virtually all key proteins involved in muscle contraction have been implicated in ECC force loss, a unifying mechanism that orchestrates force loss across such diverse molecular targets has not been identified. We showed that correcting defective hydrogen sulfide (H2S) signaling in mdx muscle prevented ECC force loss. We also showed that the cysteine proteome of skeletal muscle functioned as a redox buffer in WT and mdx muscle during ECCs, but that buffer capacity in mdx muscle was significantly compromised by elevated basal protein oxidation. Finally, chemo-proteomic data suggested that H2S protected several proteins central to muscle contraction against irreversible oxidation through persulfidation-based priming. Our results support a unifying, redox-based mechanism of ECC force loss in mdx muscle.

Authors

W. Michael Southern, Erynn E. Johnson, Elizabeth K. Fasbender, Katherine S. Fallon, Courtney L. Cavazos, Dawn A. Lowe, George G. Rodney, James M. Ervasti

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Figure 3

Diminished TSP enzyme levels in mdx skeletal muscle.

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Diminished TSP enzyme levels in mdx skeletal muscle. (A) Representative ...
(A) Representative immunoblot results and quantification of H2S-generating enzyme protein levels from WT and mdx gastrocnemius (GAS) muscles. Immunoblot samples run contemporaneously have been grouped and presented with a representative loading control image. (B) Relative levels of H2S in GAS muscle of WT and mdx mice. (C) Change in eccentric force during 10 ECCs in DysΔMTB-mdx and littermate mdx EDL muscles; eccentric forces are expressed as a percentage of the force generated during the first ECC. (D and E) Representative immunoblot results and quantification of GOT1, MPST, and TRX protein levels from WT, mdx, and DysΔMTB-mdx GAS muscles. (F) Relative levels of H2S in GAS muscle of WT, mdx, and DysΔMTB-mdx. Results are presented as mean ± SEM. *P < 0.05, ***P < 0.001, ****P < 0.0001 by Student’s t test in A and B; *P < 0.05, **P < 0.01, ****P < 0.0001 by 1-way ANOVA in D–F; *P < 0.05 by 2-way repeated-measures ANOVA in C.