{"doi":"10.1172/jci146415","title":"Insulin and IGF-1 receptors regulate complex I–dependent mitochondrial bioenergetics and supercomplexes via FoxOs in muscle","abstract":"Decreased skeletal muscle strength and mitochondrial dysfunction are characteristic of diabetes. The actions of insulin and IGF-1 through the insulin receptor (IR) and IGF-1 receptor (IGF1R) maintain muscle mass via suppression of forkhead box O (FoxO) transcription factors, but whether FoxO activation coordinates atrophy in concert with mitochondrial dysfunction is unknown. We show that mitochondrial respiration and complex I activity were decreased in streptozotocin (STZ) diabetic muscle, but these defects were reversed in muscle-specific FoxO1, -3, and -4 triple-KO (M-FoxO TKO) mice rendered diabetic with STZ. In the absence of systemic glucose or lipid abnormalities, muscle-specific IR KO (M-IR-/-) or combined IR/IGF1R KO (MIGIRKO) impaired mitochondrial respiration, decreased ATP production, and increased ROS. These mitochondrial abnormalities were not present in muscle-specific IR, IGF1R, and FoxO1, -3, and -4 quintuple-KO mice (M-QKO). Acute tamoxifen-inducible deletion of IR and IGF1R also decreased muscle pyruvate respiration, complex I activity, and supercomplex assembly. Although autophagy was increased when IR and IGF1R were deleted in muscle, mitophagy was not increased. Mechanistically, RNA-Seq revealed that complex I core subunits were decreased in STZ-diabetic and MIGIRKO muscle, and these changes were not present with FoxO KO in STZ-FoxO TKO and M-QKO mice. Thus, insulin-deficient diabetes or loss of insulin/IGF-1 action in muscle decreases complex I-driven mitochondrial respiration and supercomplex assembly in part by FoxO-mediated repression of complex I subunit expression.","journal":"Journal of Clinical Investigation","year":2021,"id":156993,"datarank":0.5955437870328184,"base_score":3.970291913552122,"endowment":3.970291913552122,"self_citation_contribution":0.5955437870328184,"citation_network_contribution":0.0,"self_endowment_contribution":0.5955437870328184,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":52,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":483839,"name":"Christie M. Penniman","orcid":null,"position":1,"is_corresponding":false},{"id":663064,"name":"Jayashree Jena","orcid":"0000-0001-9929-662X","position":2,"is_corresponding":false},{"id":664013,"name":"Pablo A. Suarez Beltran","orcid":null,"position":3,"is_corresponding":false},{"id":664014,"name":"COLLIN M. FOSTER","orcid":null,"position":4,"is_corresponding":false},{"id":664015,"name":"Kennedy Poro","orcid":null,"position":5,"is_corresponding":false},{"id":664016,"name":"Taylor L. Junck","orcid":null,"position":6,"is_corresponding":false},{"id":297596,"name":"Antentor Hinton","orcid":"0000-0002-7730-952X","position":7,"is_corresponding":false},{"id":644503,"name":"Rhonda Souvenir","orcid":"0000-0002-8880-2483","position":8,"is_corresponding":false},{"id":663065,"name":"Jordan D. Fuqua","orcid":"0000-0002-4437-0834","position":9,"is_corresponding":false},{"id":251718,"name":"Pablo E. Morales","orcid":"0000-0003-1802-8135","position":10,"is_corresponding":false},{"id":663066,"name":"Roberto Bravo","orcid":"0000-0001-8873-8699","position":11,"is_corresponding":false},{"id":571440,"name":"William I. Sivitz","orcid":"0000-0002-7829-0189","position":12,"is_corresponding":false},{"id":612656,"name":"Vitor A. Lira","orcid":"0000-0002-3162-3804","position":13,"is_corresponding":false},{"id":153753,"name":"E. Dale Abel","orcid":"0000-0001-5290-0738","position":14,"is_corresponding":false},{"id":482784,"name":"Brian T. O’Neill","orcid":"0000-0002-5685-9805","position":15,"is_corresponding":false},{"id":482782,"name":"Gourav Bhardwaj","orcid":"0000-0002-9543-8237","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:44:17.471040Z","pmid":"34343133","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":[]}