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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.<\/jats:p>","DOI":"10.1172\/jci.insight.142446","type":"journal-article","created":{"date-parts":[[2020,9,15]],"date-time":"2020-09-15T12:01:10Z","timestamp":1600171270000},"source":"Crossref","is-referenced-by-count":34,"title":["Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts"],"prefix":"10.1172","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7841-2337","authenticated-orcid":true,"given":"Joseph D.","family":"Powers","sequence":"first","affiliation":[{"name":"Department of Bioengineering, College of Engineering and School of Medicine, University of Washington, Seattle, Washington, USA."},{"name":"Department of Bioengineering, 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