{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T19:07:19Z","timestamp":1789412839397,"version":"build-2803163510"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL123774 R01 HL 036153 R01 HL136590"],"award-info":[{"award-number":["R01 HL123774 R01 HL 036153 R01 HL136590"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Dilated cardiomyopathy (DCM) is an inherited disorder often leading to severe heart failure. Linkage studies in affected families have revealed hundreds of different mutations that can cause DCM, with most occurring in genes associated with the cardiac sarcomere. We have developed an investigational pipeline for discovering mechanistic genotype-phenotype relationships in DCM and here apply it to the DCM-linked tropomyosin mutation <jats:italic>TPM1<\/jats:italic> M8R. Atomistic simulations predict that M8R increases flexibility of the tropomyosin chain and enhances affinity for the blocked or inactive state of tropomyosin on actin. Applying these molecular effects to a Markov model of the cardiac thin filament reproduced the shifts in Ca<jats:sup>2+<\/jats:sup>sensitivity, maximum force, and a qualitative drop in cooperativity that were observed in an <jats:italic>in vitro<\/jats:italic> system containing <jats:italic>TPM1<\/jats:italic> M8R. The model was then used to simulate the impact of M8R expression on twitch contractions of intact cardiac muscle, predicting that M8R would reduce peak force and duration of contraction in a dose-dependent manner. To evaluate this prediction, <jats:italic>TPM1<\/jats:italic> M8R was expressed via adenovirus in human engineered heart tissues and isometric twitch force was observed. The mutant tissues manifested depressed contractility and twitch duration that agreed in detail with model predictions. Additional exploratory simulations suggest that M8R-mediated alterations in tropomyosin-actin interactions contribute more potently than tropomyosin chain stiffness to cardiac twitch dysfunction, and presumably to the ultimate manifestation of DCM. This study is an example of the growing potential for successful <jats:italic>in silico<\/jats:italic> prediction of mutation pathogenicity for inherited cardiac muscle disorders.<\/jats:p>","DOI":"10.3389\/fphys.2024.1452509","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T05:09:01Z","timestamp":1724994541000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["In silico and in vitro models reveal the molecular mechanisms of hypocontractility caused by TPM1 M8R"],"prefix":"10.3389","volume":"15","author":[{"given":"Jenette G.","family":"Creso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilhan","family":"Gokhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Rynkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Lehman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart G.","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1161\/CIRCRESAHA.109.196055","article-title":"Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy","volume":"105","author":"Carballo","year":"2009","journal-title":"Circulation Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1007\/s10741-005-5252-6","article-title":"Sarcomeric protein mutations in dilated cardiomyopathy","volume":"10","author":"Chang","year":"2005","journal-title":"Heart Fail Rev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.abb.2013.08.013","article-title":"Increased myocardial short-range forces in a rodent model of diabetes reflect elevated content of \u03b2 myosin heavy chain","author":"Chung","year":"2014","journal-title":"Archives Biochem. 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