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ResearchIn-Press PreviewMetabolismMuscle biology Open Access | 10.1172/JCI176942

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

W. Michael Southern,1 Erynn E. Johnson,1 Elizabeth K. Fasbender,1 Katherine S. Fallon,1 Courtney L. Cavazos,2 Dawn A. Lowe,3 George G. Rodney,2 and James M. Ervasti1

1Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, United States of America

2Department of Integrative Physiology, Baylor College of Medicine, Houston, United States of America

3Department of Family Medicine and Community Health, Division of Physical Th, University of Minnesota, Minneapolis, United States of America

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1Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, United States of America

2Department of Integrative Physiology, Baylor College of Medicine, Houston, United States of America

3Department of Family Medicine and Community Health, Division of Physical Th, University of Minnesota, Minneapolis, United States of America

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1Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, United States of America

2Department of Integrative Physiology, Baylor College of Medicine, Houston, United States of America

3Department of Family Medicine and Community Health, Division of Physical Th, University of Minnesota, Minneapolis, United States of America

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1Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, United States of America

2Department of Integrative Physiology, Baylor College of Medicine, Houston, United States of America

3Department of Family Medicine and Community Health, Division of Physical Th, University of Minnesota, Minneapolis, United States of America

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1Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, United States of America

2Department of Integrative Physiology, Baylor College of Medicine, Houston, United States of America

3Department of Family Medicine and Community Health, Division of Physical Th, University of Minnesota, Minneapolis, United States of America

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1Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, United States of America

2Department of Integrative Physiology, Baylor College of Medicine, Houston, United States of America

3Department of Family Medicine and Community Health, Division of Physical Th, University of Minnesota, Minneapolis, United States of America

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1Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, United States of America

2Department of Integrative Physiology, Baylor College of Medicine, Houston, United States of America

3Department of Family Medicine and Community Health, Division of Physical Th, University of Minnesota, Minneapolis, United States of America

Find articles by Rodney, G. in: JCI | PubMed | Google Scholar

1Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, United States of America

2Department of Integrative Physiology, Baylor College of Medicine, Houston, United States of America

3Department of Family Medicine and Community Health, Division of Physical Th, University of Minnesota, Minneapolis, United States of America

Find articles by Ervasti, J. in: JCI | PubMed | Google Scholar

Published January 14, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI176942.
Copyright © 2025, Southern et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 14, 2025 - Version history
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Abstract

Eccentric contraction- (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.

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