{"doi":"10.3389/fphys.2022.1033300","title":"Ablation of Calsequestrin-1, Ca2+ unbalance, and susceptibility to heat stroke","abstract":"Introduction: Ca 2+ levels in adult skeletal muscle fibers are mainly controlled by excitation-contraction (EC) coupling, a mechanism that translates action potentials in release of Ca 2+ from the sarcoplasmic reticulum (SR) release channels, i.e. the ryanodine receptors type-1 (RyR1). Calsequestrin (Casq) is a protein that binds large amounts of Ca 2+ in the lumen of the SR terminal cisternae, near sites of Ca 2+ release. There is general agreement that Casq is not only important for the SR ability to store Ca 2+ , but also for modulating the opening probability of the RyR Ca 2+ release channels. The initial studies: About 20 years ago we generated a mouse model lacking Casq1 (Casq1-null mice), the isoform predominantly expressed in adult fast twitch skeletal muscle. While the knockout was not lethal as expected, lack of Casq1 caused a striking remodeling of membranes of SR and of transverse tubules (TTs), and mitochondrial damage. Functionally, CASQ1-knockout resulted in reduced SR Ca 2+ content, smaller Ca 2+ transients, and severe SR depletion during repetitive stimulation. The myopathic phenotype of Casq1-null mice: After the initial studies, we discovered that Casq1-null mice were prone to sudden death when exposed to halogenated anaesthetics, heat and even strenuous exercise. These syndromes are similar to human malignant hyperthermia susceptibility (MHS) and environmental-exertional heat stroke (HS). We learned that mechanisms underlying these syndromes involved excessive SR Ca 2+ leak and excessive production of oxidative species: indeed, mortality and mitochondrial damage were significantly prevented by administration of antioxidants and reduction of oxidative stress. Though, how Casq1-null mice could survive without the most important SR Ca 2+ binding protein was a puzzling issue that was not solved. Unravelling the mystery: The mystery was finally solved in 2020, when we discovered that in Casq1-null mice the SR undergoes adaptations that result in constitutively active store-operated Ca 2+ entry (SOCE). SOCE is a mechanism that allows skeletal fibers to use external Ca 2+ when SR stores are depleted. The post-natal compensatory mechanism that allows Casq1-null mice to survive involves the assembly of new SR-TT junctions (named Ca 2+ entry units) containing Stim1 and Orai1, the two proteins that mediate SOCE.","journal":"Frontiers in Physiology","year":2022,"id":266775,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9666,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":927329,"name":"Barbara Girolami","orcid":null,"position":1,"is_corresponding":false},{"id":926894,"name":"Matteo Serano","orcid":"0000-0002-4151-2980","position":2,"is_corresponding":false},{"id":456811,"name":"Laura Pietrangelo","orcid":"0000-0003-1197-7813","position":3,"is_corresponding":false},{"id":926895,"name":"Cecilia Paolini","orcid":"0000-0002-5720-7577","position":4,"is_corresponding":false},{"id":456813,"name":"Feliciano Protasi","orcid":"0000-0002-0213-7591","position":0,"is_corresponding":true}],"reference_count":177,"raw_metadata":null,"created_at":"2026-07-19T00:26:58.102271Z","pmid":"36311237","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":[]}