{"doi":"10.1172/jci.insight.142446","title":"Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts","abstract":"Dilated cardiomyopathy (DCM) is often associated with sarcomere protein mutations that confer reduced myofilament tension-generating capacity. We demonstrated that cardiac twitch tension-time integrals can be targeted and tuned to prevent DCM remodeling in hearts with contractile dysfunction. We employed a transgenic murine model of DCM caused by the D230N-tropomyosin (Tm) mutation and designed a sarcomere-based intervention specifically targeting the twitch tension-time integral of D230N-Tm hearts using multiscale computational models of intramolecular and intermolecular interactions in the thin filament and cell-level contractile simulations. Our models predicted that increasing the calcium sensitivity of thin filament activation using the cardiac troponin C (cTnC) variant L48Q can sufficiently augment twitch tension-time integrals of D230N-Tm hearts. Indeed, cardiac muscle isolated from double-transgenic hearts expressing D230N-Tm and L48Q cTnC had increased calcium sensitivity of tension development and increased twitch tension-time integrals compared with preparations from hearts with D230N-Tm alone. Longitudinal echocardiographic measurements revealed that DTG hearts retained normal cardiac morphology and function, whereas D230N-Tm hearts developed progressive DCM. We present a computational and experimental framework for targeting molecular mechanisms governing the twitch tension of cardiomyopathic hearts to counteract putative mechanical drivers of adverse remodeling and open possibilities for tension-based treatments of genetic cardiomyopathies.","journal":"JCI Insight","year":2020,"id":96081,"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":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9505,"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":476801,"name":"Kristina B. Kooiker","orcid":"0000-0003-1817-9080","position":1,"is_corresponding":false},{"id":476802,"name":"Allison B. Mason","orcid":"0000-0003-0350-0417","position":2,"is_corresponding":false},{"id":432344,"name":"Abigail E. Teitgen","orcid":"0000-0002-5134-7261","position":3,"is_corresponding":false},{"id":476803,"name":"Galina Flint","orcid":"0000-0003-3993-5156","position":4,"is_corresponding":false},{"id":408805,"name":"Jil C. Tardiff","orcid":"0000-0003-4291-4882","position":5,"is_corresponding":false},{"id":476804,"name":"Steven D. Schwartz","orcid":"0000-0002-0308-1059","position":6,"is_corresponding":false},{"id":262489,"name":"Andrew D. McCulloch","orcid":"0000-0002-1708-5675","position":7,"is_corresponding":false},{"id":347667,"name":"Michael Regnier","orcid":"0000-0001-5437-9851","position":8,"is_corresponding":false},{"id":270773,"name":"Jennifer Davis","orcid":"0000-0003-2380-1321","position":9,"is_corresponding":false},{"id":472057,"name":"Farid Moussavi‐Harami","orcid":"0000-0002-0189-7214","position":10,"is_corresponding":false},{"id":476800,"name":"Joseph D. Powers","orcid":"0000-0001-7841-2337","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-18T22:34:34.781847Z","pmid":"32931484","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":[]}