Impaired hydrogen sulfide biosynthesis underlies eccentric contraction–induced force loss in dystrophin-deficient skeletal muscle
W. Michael Southern, Erynn E. Johnson, Elizabeth K. Fasbender, Katherine S. Fallon, Courtney L. Cavazos, Dawn A. Lowe, George G. Rodney, James M. Ervasti
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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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 8

Enrichment analysis identifies multiple proteins involved in muscle contraction and redox homeostasis.

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Enrichment analysis identifies multiple proteins involved in muscle cont...
(A) The top 20 enriched Biological Process GO terms from enrichment analysis performed on the 119 unique genes identified in Figure 7C. Blue bars signify GO terms related to muscle contraction or redox homeostasis. (B) List of unique genes identified from the muscle contraction or redox homeostasis GO terms highlighted in A. Four additional muscle contraction– or redox-related genes not represented in the top 20 GO terms were also included. (C) Principal component analysis (PCA) of average oxidation level between all samples colored by experimental group. Each sample is composed of the 24 peptides represented by the 15 unique genes highlighted in B. (D) Heatmap of z scores showing relative differences in cysteine oxidation level of individual peptides of interest between WT, WT+ECC, mdx, mdx+ECC, and mdx+ECC+NaHS groups.