{"doi":"10.1101/2020.06.04.134213","title":"SWELL1-LRRC8 complex regulates skeletal muscle cell size, intracellular signalling, adiposity and glucose metabolism","abstract":"Abstract Maintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate skeletal muscle differentiation, growth and metabolism, however the molecular mechanosensor remains unknown. Here, we show that SWELL1 (LRRC8a) functionally encodes a swell-activated anion channel that regulates PI3K-AKT, ERK1/2, mTOR signaling, muscle differentiation, myoblast fusion, cellular oxygen consumption, and glycolysis in skeletal muscle cells. SWELL1 over-expression in SWELL1 KO myotubes boosts PI3K-AKT-mTOR signaling to supra-normal levels and fully rescues myotube formation. Skeletal muscle targeted SWELL1 KO mice have smaller myofibers, generate less force ex vivo , and exhibit reduced exercise endurance, associated with increased adiposity under basal conditions, and glucose intolerance and insulin resistance when raised on a high-fat diet, compared to WT mice. These results reveal that the SWELL1-LRRC8 complex regulates insulin-PI3K-AKT-mTOR signalling in skeletal muscle to influence skeletal muscle differentiation in vitro and skeletal myofiber size, muscle function, adiposity and systemic metabolism in vivo .","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127002,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":303252,"name":"Litao Xie","orcid":null,"position":1,"is_corresponding":false},{"id":303253,"name":"Chau My Ta","orcid":null,"position":2,"is_corresponding":false},{"id":297596,"name":"Antentor Hinton","orcid":"0000-0002-7730-952X","position":3,"is_corresponding":false},{"id":303254,"name":"Susheel K. Gunasekar","orcid":null,"position":4,"is_corresponding":false},{"id":303255,"name":"Rachel A Minerath","orcid":null,"position":5,"is_corresponding":false},{"id":301599,"name":"Karen Shen","orcid":"0000-0001-5982-1872","position":6,"is_corresponding":false},{"id":301600,"name":"Joshua M Maurer","orcid":"0000-0002-2107-0767","position":7,"is_corresponding":false},{"id":301601,"name":"Chad E. Grueter","orcid":"0000-0001-8950-742X","position":8,"is_corresponding":false},{"id":153753,"name":"E. Dale Abel","orcid":"0000-0001-5290-0738","position":9,"is_corresponding":false},{"id":245889,"name":"Gretchen A. Meyer","orcid":"0000-0001-9268-3993","position":10,"is_corresponding":false},{"id":301602,"name":"Rajan Sah","orcid":"0000-0003-1092-1244","position":11,"is_corresponding":false},{"id":301598,"name":"Ashutosh Kumar","orcid":"0000-0002-2623-0416","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-18T23:15:27.226519Z","pmid":null,"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":[]}