{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T05:35:58Z","timestamp":1776836158724,"version":"3.51.2"},"posted":{"date-parts":[[2025,5,19]]},"group-title":"Physiology","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T00:00:00Z","timestamp":1747612800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Mutations in\n                    <jats:italic>DSP<\/jats:italic>\n                    , which encodes the protein desmoplakin, lead to cardiomyopathy with unusually high penetrance. Clinical features include ventricular tachyarrhythmias, fibro-fatty infiltration of both ventricles, and ultimately dilated cardiomyopathy. While some data have been gathered to explain the electrophysiological and contractile consequences of desmoplakin cardiomyopathy, a comprehensive mechanism linking\n                    <jats:italic>DSP<\/jats:italic>\n                    mutations to ventricular dilation and heart failure remains elusive.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We use iPSC-derived engineered heart tissue (EHT) bearing a functional desmoplakin haploinsufficiency to model the heart failure phenotype that occurs in desmoplakin cardiomyopathy. Functional haploinsufficiency is secondary to a missense mutation, R451G, that results in proteolytic degradation of desmoplakin with no detectable protein. We complement functional data obtained in tissue-engineered constructs with cell biology assays in 2D cardiomyocytes to glean insights into the mechanism and mechanobiology of desmoplakin cardiomyopathy.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Engineered heart tissues harboring a desmoplakin insufficiency recapitulate a patient phenotype notable for hypocontractility and ventricular dilation. Surprisingly, DSP-mutant tissues exhibited a shortened resting sarcomere length that was dependent on protein kinase C activity. Concurrently, mechanical load on \u03b1-catenin was increased, suggesting a mechanism by which desmosomal insufficiency redistributes force to adherens junctions. Excessive loading on adherens junctions may act as a stimulus for avid insertion of series sarcomeres, shortening the length per sarcomere, and resulting in a contractile deficit. PKC inhibition rescues shortened sarcomere length in DSP- mutant tissues, suggesting that it could be a target for future molecular therapies.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our study uncovers a novel mechanism underlying systolic dysfunction in desmoplakin cardiomyopathy. We not only recapitulate the disease phenotype, but we identify sarcomere length regulation through altered force transmission at the intercalated disc as a previously-unrecognized mechanism.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.15.654389","type":"posted-content","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T12:15:17Z","timestamp":1747656917000},"source":"Crossref","is-referenced-by-count":1,"title":["Desmoplakin loss leads to PKC-dependent insertion of series sarcomeres and contractile dysfunction in cardiomyocytes"],"prefix":"10.64898","author":[{"given":"Ilhan","family":"Gokhan","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Yale University, New Haven, CT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Yale University, New Haven, CT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack M.","family":"Sendek","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Yale University, New Haven, CT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex J.","family":"Mora Pagan","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Yale University, New Haven, CT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9146-8407","authenticated-orcid":false,"given":"Fadi G.","family":"Akar","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Yale University, New Haven, CT"},{"name":"Division of Cardiology, Department of Internal Medicine, Yale University, New Haven, CT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1527-0770","authenticated-orcid":false,"given":"Stuart 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