{"doi":"10.1016/j.jmccpl.2025.100296","title":"SGLT2 inhibitor upregulates myocardial genes for oxidative phosphorylation and fatty acid metabolism in Gαq-mice","abstract":"Mitochondrial dysfunction with decreased ATP production and increased release of reactive oxygen species (ROS) is a hallmark of the failing heart. Although SGLT2 inhibitors have been shown to improve myocardial metabolism in the failing heart, independent of diabetes, the effect on mitochondria is not clear. Our goal was to test the effect of the SGLT2 inhibitor ertugliflozin on mitochondrial gene expression and function in myocardium and isolated mitochondria from non-diabetic mice with dilated cardiomyopathy due to cardiac-specific over-expression of Gαq. Gαq and wild type (WT) littermates 4 weeks of age were treated for 16 weeks with or without the SGLT2 inhibitor ertugliflozin (ERTU) formulated in the chow (0.5 mg/g chow). From weeks 4 to 20, Gαq mice developed progressive cardiac hypertrophy, dilation, contractile dysfunction, myocyte apoptosis and interstitial fibrosis – all of which were prevented by ERTU treatment. Isolated cardiac mitochondria from Gαq mice had decreased maximal ATP production and increased ROS release - both of which were normalized by ERTU. In isolated beating hearts from Gαq mice, contractile reserve and high energy phosphates measured simultaneously by 31 P NMR spectroscopy were decreased - and both were improved by ERTU. In Gαq mice, marked suppression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism was reversed by ERTU. The SGLT2 inhibitor ERTU corrected the expression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism, and was associated with increased production of ATP, decreased release of mitochondrial ROS, and amelioration of the consequences of mitochondrial dysfunction on myocardial structure and function. • Mitochondrial dysfunction is a hallmark of the failing heart. • Overexpression of Gαq in mice causes heart failure and mitochondrial dysfunction. • Gαq mice were treated with the SGLT2 inhibitor ertugliflozin for 16 weeks. • Ertugliflozin prevented structural remodeling and mitochondrial dysfunction. • Ertugliflozin corrected adverse programing of cardiac metabolic genes.","journal":"Journal of Molecular and Cellular Cardiology Plus","year":2025,"id":539208,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":341593,"name":"Dominique Croteau","orcid":"0000-0001-9274-5314","position":1,"is_corresponding":false},{"id":343152,"name":"David R. Pimentel","orcid":null,"position":2,"is_corresponding":false},{"id":431937,"name":"Adam C. Gower","orcid":"0000-0002-6122-7511","position":3,"is_corresponding":false},{"id":343150,"name":"Marcello Panagia","orcid":null,"position":4,"is_corresponding":false},{"id":341592,"name":"Tomáš Baka","orcid":"0000-0003-4752-9828","position":5,"is_corresponding":false},{"id":472114,"name":"Fuzhong Qin","orcid":"0000-0002-9534-3617","position":6,"is_corresponding":false},{"id":341596,"name":"Ivan Luptak","orcid":"0000-0001-7498-7694","position":7,"is_corresponding":false},{"id":341595,"name":"Wilson S. Colucci","orcid":"0000-0002-0576-9420","position":8,"is_corresponding":false},{"id":472115,"name":"Jordan M. Chambers","orcid":"0000-0002-4285-7454","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-19T02:52:30.048313Z","pmid":"40291834","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":[]}