{"doi":"10.1016/j.bbrc.2024.150163","title":"Physiological role for S-nitrosylation of RyR1 in skeletal muscle function and development","abstract":"Excitation-contraction coupling in skeletal muscle myofibers depends upon Ca2+ release from the sarcoplasmic reticulum through the ryanodine receptor/Ca2+-release channel RyR1. The RyR1 contains ∼100 Cys thiols of which ∼30 comprise an allosteric network subject to posttranslational modification by S-nitrosylation, S-palmitoylation and S-oxidation. However, the role and function of these modifications is not understood. Although aberrant S-nitrosylation of multiple unidentified sites has been associated with dystrophic diseases, malignant hyperthermia and other myopathic syndromes, S-nitrosylation in physiological situations is reportedly specific to a single (1 of ∼100) Cys in RyR1, Cys3636 in a manner gated by pO2. Using mice expressing a form of RyR1 with a Cys3636→Ala point mutation to prevent S-nitrosylation at this site, we showed that Cys3636 was the principal target of endogenous S-nitrosylation during normal muscle function. The absence of Cys3636 S-nitrosylation suppressed stimulus-evoked Ca2+ release at physiological pO2 (at least in part by altering the regulation of RyR1 by Ca2+/calmodulin), eliminated pO2 coupling, and diminished skeletal myocyte contractility in vitro and measures of muscle strength in vivo. Furthermore, we found that abrogation of Cys3636 S-nitrosylation resulted in a developmental defect reflected in diminished myofiber diameter, altered fiber subtypes, and altered expression of genes implicated in muscle development and atrophy. Thus, our findings establish a physiological role for pO2-coupled S-nitrosylation of RyR1 in skeletal muscle contractility and development and provide foundation for future studies of RyR1 modifications in physiology and disease.","journal":"Biochemical and Biophysical Research Communications","year":2024,"id":454546,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9496,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":707968,"name":"Zachary W. Grimmett","orcid":"0000-0003-3820-2049","position":1,"is_corresponding":false},{"id":1278479,"name":"Douglas T. Hess","orcid":null,"position":2,"is_corresponding":false},{"id":103749,"name":"Lautaro G. Perez","orcid":null,"position":3,"is_corresponding":false},{"id":754689,"name":"Zhaoxia Qian","orcid":"0000-0003-1314-9499","position":4,"is_corresponding":false},{"id":1278480,"name":"Ruchi Chaube","orcid":null,"position":5,"is_corresponding":false},{"id":770749,"name":"Nicholas M. Venetos","orcid":null,"position":6,"is_corresponding":false},{"id":1278481,"name":"Bradley N. Plummer","orcid":null,"position":7,"is_corresponding":false},{"id":728353,"name":"Kenneth R. Laurita","orcid":"0000-0002-6341-9656","position":8,"is_corresponding":false},{"id":455361,"name":"Richard T. Premont","orcid":"0000-0002-8053-5026","position":9,"is_corresponding":false},{"id":522156,"name":"Jonathan S. Stamler","orcid":"0000-0002-6866-1572","position":10,"is_corresponding":false},{"id":255400,"name":"Qian Sun","orcid":"0000-0001-5623-6213","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T02:03:12.720997Z","pmid":"38820626","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}