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We evaluated the hypothesis that myofilament dysfunction is coupled to morphological and functional alterations of cardiomyocyte nuclei in a Tnnc1-targeted knock-in (Tnnc1-p.A8V) mouse model of hypertrophic cardiomyopathy (HCM). Tnnc1 is the gene that codes for the isoform of the Ca2+-regulatory protein troponin C (cTnC) that is expressed in cardiomyocytes and slow skeletal muscle fibers and resides on thin filaments of sarcomeres in those muscles. This pathogenic mutation in a sarcomere gene alters many aspects of cardiomyocyte function, including sarcomere contractility, cytoplasmic Ca2+ buffering, and gene expression. Analysis of myocardial histological sections and isolated cardiomyocytes from adult Tnnc1-p.A8V mouse hearts revealed significantly smaller (cross-sectional area and volume) and rounder nuclei compared to those from age-matched, wild-type control mice. Changes in nuclear morphology could not be explained by differences in cardiomyocyte size or ploidy. Isolated wild-type and mutant cardiomyocyte nuclei, which are embedded centrally within myofibrils, undergo compression during contraction of the cardiomyocyte, indicating that during each heartbeat cardiomyocyte nuclei would be mechanically deformed as well as being exposed to elevated cytoplasmic Ca2+. Immunoblotting analysis indicated decreased nuclear localization of cardiac troponin C and decreased histone H4 expression in Tnnc1-p.A8V mouse hearts. Next, we investigated the influence of nucleocytoplasmic transport by immunofluorescence microscopy, and we could not confirm nuclear localization of cardiac troponin C in fixed myocardial tissue from adult mice. However, cardiac troponin C could be detected in healthy human-induced pluripotent stem cell-derived cardiomyocyte nuclei. We conclude that pathological myofilament dysfunction due to a pathogenic, cardiomyopathy-associated mutation can be linked to altered protein composition of cardiomyocyte nuclei and aberrant nuclear morphology.<\/jats:p>","DOI":"10.3390\/jcdd12110449","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T12:55:31Z","timestamp":1763556931000},"page":"449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cardiomyocyte Nuclear Pleomorphism in a Mouse Model of Inherited Hypertrophic Cardiomyopathy"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3563-640X","authenticated-orcid":false,"given":"Jamie R.","family":"Johnston","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9706-9319","authenticated-orcid":false,"given":"Isabella","family":"Leite Coscarella","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2033-6087","authenticated-orcid":false,"given":"Carson L.","family":"Rose","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2970-2458","authenticated-orcid":false,"given":"Yun","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1358-9910","authenticated-orcid":false,"given":"Hosna","family":"Rastegarpouyani","sequence":"additional","affiliation":[{"name":"Institute for Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9124-6246","authenticated-orcid":false,"given":"Karissa M. Dieseldorff","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9714-4117","authenticated-orcid":false,"given":"Jennifer M.","family":"Le Patourel","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7063-6977","authenticated-orcid":false,"given":"Feyikemi","family":"Ogunfuwa","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5747-5945","authenticated-orcid":false,"given":"Adriano S.","family":"Martins","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9461-4032","authenticated-orcid":false,"given":"Kathryn M.","family":"Crotty","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0128-2000","authenticated-orcid":false,"given":"Katherine M.","family":"Ward Molla","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7923-3971","authenticated-orcid":false,"given":"Tyler R.","family":"Reinoso","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4153-3215","authenticated-orcid":false,"given":"Taylor L.","family":"Waldmann","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4804-7225","authenticated-orcid":false,"given":"Jerome","family":"Irianto","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2641-6904","authenticated-orcid":false,"given":"Yue Julia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Wang","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4956-9735","authenticated-orcid":false,"given":"Bj\u00f6rn C.","family":"Knollmann","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9092-4976","authenticated-orcid":false,"given":"Jose R.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9701-561X","authenticated-orcid":false,"given":"Prescott Bryant","family":"Chase","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1146\/annurev-genom-083118-015306","article-title":"Advances in the Genetic Basis and Pathogenesis of Sarcomere Cardiomyopathies","volume":"20","author":"Yotti","year":"2019","journal-title":"Annu. 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