{"doi":"10.1101/2024.01.12.575391","title":"Loss of calpain 3 dysregulates store-operated calcium entry and its exercise response in mice","abstract":"ABSTRACT Limb-Girdle Muscular Dystrophy 2A (LGMD2A) is caused by mutations in the CAPN3 gene encoding Calpain 3, a skeletal-muscle specific, Ca 2+ -dependent protease. Localization of Calpain 3 within the triad suggests it contributes to Ca 2+ homeostasis. Through live-cell Ca 2+ measurements, muscle mechanics, immunofluorescence, and electron microscopy (EM) in Capn3 deficient (C3KO) and wildtype (WT) mice, we determined if loss of Calpain 3 altered Store-Operated Calcium Entry (SOCE) activity. Direct Ca 2+ influx measurements revealed loss of Capn3 elicits elevated resting SOCE and increased resting cytosolic Ca 2+ , supported by high incidence of calcium entry units (CEUs) observed by EM. C3KO and WT mice were subjected to a single bout of treadmill running to elicit SOCE. Within 1HR post-treadmill running, C3KO mice exhibited diminished force production in extensor digitorum longus muscles and a greater decay of Ca 2+ transients in flexor digitorum brevis muscle fibers during repetitive stimulation. Striking evidence for impaired exercise-induced SOCE activation in C3KO mice included poor colocalization of key SOCE proteins, stromal-interacting molecule 1 (STIM1) and ORAI1, combined with disappearance of CEUs in C3KO muscles. These results demonstrate that Calpain 3 is a key regulator of SOCE in skeletal muscle and identify SOCE dysregulation as a contributing factor to LGMD2A pathology.","journal":"ACADEME University of Bohol Graduate School and Professional Studies","year":2024,"id":487717,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"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":1260169,"name":"Renjia Zhong","orcid":"0000-0003-4448-6551","position":1,"is_corresponding":false},{"id":1284378,"name":"C. Spencer Henley‐Beasley","orcid":null,"position":2,"is_corresponding":false},{"id":936059,"name":"Giorgia Rastelli","orcid":"0000-0002-2476-7519","position":3,"is_corresponding":false},{"id":456810,"name":"Simona Boncompagni","orcid":"0000-0001-5308-5069","position":4,"is_corresponding":false},{"id":260624,"name":"Elisabeth R. Barton","orcid":"0000-0002-7401-4398","position":5,"is_corresponding":false},{"id":281650,"name":"Lan Wei‐LaPierre","orcid":"0000-0002-4781-5886","position":6,"is_corresponding":false},{"id":937521,"name":"Katelyn R. Villani","orcid":null,"position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:10.215754Z","pmid":"38293127","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":[]}