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 5

Reactive protein targets of H2S are elevated in mdx skeletal muscle.

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Reactive protein targets of H2S are elevated in mdx skeletal muscle. (A–...
(A–C) Representative image (A) and quantification of in-gel fluorescence showing protein thiol oxidation in WT and mdx EDL (B) or tibialis anterior (TA) (C) muscles. (D and E) Representative image (D) and quantification of in-gel fluorescence showing protein thiol sulfenylation from WT and mdx gastrocnemius muscle (E). (F) Change in force during 10 isometric (ISO) or eccentric contractions in WT or mdx EDLs incubated with or without hydrogen peroxide (H2O2). (G) Percentage force loss after 10 ISOs or ECCs from the groups presented in F. (H) Change in eccentric force during 10 ECCs in WT EDL muscles treated with vehicle or 0.5 mM of the H2S scavenger 7-azido-4-methylcoumarin (AzMC). (I) Eccentric force produced at ECC #4 in H. (J) Change in eccentric force during 10 ECCs in mdx EDL muscles incubated with vehicle or NaHS. (K) Change in DCF fluorescence, a proxy for ROS production, from pre-ECC baseline through 10 ECCs in the EDL muscles from J. (L) DCF fluorescence during baseline, after ECC #1, and after ECC #10 in K. All ISO or ECC force data in F, H, and J are expressed as a percentage of the force generated during the first contraction. Results are presented as mean ± SEM. *P < 0.05, ***P < 0.001 by Student’s t test in B, C, E, and I; *P < 0.05, ***P < 0.001, ****P < 0.0001 by 1-way ANOVA in G; *P < 0.05 by 2-way repeated-measures ANOVA in H. *Different from WT+ECC and mdx+ECC+NaHS, #different from WT+ECC and mdx+ECC, P < 0.05 by 2-way repeated-measures ANOVA in J. *Different from mdx+ECC, P < 0.05 by 2-way repeated-measures ANOVA in K. Main effects by 2-way ANOVA reported in J.