{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:05:22Z","timestamp":1785431122116,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,27]]},"group-title":"Cell Biology","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL142217"],"award-info":[{"award-number":["R01HL142217"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The actin cytoskeleton of the cardiomyocyte is organized into two structurally and functionally distinct filament networks. The sarcomeric thin filaments, built primarily from cardiac \u03b1-actin (\u03b1CA), generate contractile force, whereas a separate subsarcolemmal cytoplasmic network, built from \u03b2-actin (\n                  <jats:italic>Actb<\/jats:italic>\n                  gene) and \u03b3-actin (\n                  <jats:italic>Actg1<\/jats:italic>\n                  gene), lies beneath the sarcolemma and is comparatively understudied in the mature heart. We hypothesized that this cytoplasmic actin network is required for sarcolemmal membrane integrity, signal transduction, and mechanosensing in the adult cardiomyocyte, and we generated cardiomyocyte-specific\n                  <jats:italic>Actb<\/jats:italic>\n                  and\n                  <jats:italic>Actg1<\/jats:italic>\n                  double-gene deleted mice, using loxP (fl)-targeted\n                  <jats:italic>Actb<\/jats:italic>\n                  <jats:sup>fl\/fl<\/jats:sup>\n                  and\n                  <jats:italic>Actg1<\/jats:italic>\n                  <jats:sup>fl\/fl<\/jats:sup>\n                  alleles combined with an \u03b1MHC (Myh6) promoter-driven Cre-recombinase transgene, to test this directly. Deletion of cytoplasmic \u03b2-actin and \u03b3-actin from cardiomyocytes (\n                  <jats:italic>\n                    Actb\/g1\n                    <jats:sup>fl\/fl-Myh6-Cre<\/jats:sup>\n                  <\/jats:italic>\n                  mice) drove compensatory upregulation of a \u03b3-interferon like stress response with compensatory upregulation of skeletal \u03b1-actin (\u03b1SKA) and smooth muscle \u03b1-actin (\u03b1SMA) protein in adult cardiomyocytes, without altering baseline cardiac structure or function. To test if lost \u03b2-actin and \u03b3-actin in the mouse heart impacts sarcolemmal stability, we crossed\n                  <jats:italic>\n                    Actb\/g1\n                    <jats:sup>fl\/fl-Myh6-Cre<\/jats:sup>\n                  <\/jats:italic>\n                  mice onto the dystrophin-deficient\n                  <jats:italic>mdx<\/jats:italic>\n                  background, which is characterized by a fragile sarcolemma. Unexpectedly, hearts from\n                  <jats:italic>\n                    Actb\/g1\n                    <jats:sup>fl\/fl-Myh6-<\/jats:sup>\n                    <jats:sup>Cre<\/jats:sup>\n                  <\/jats:italic>\n                  ;\n                  <jats:italic>mdx<\/jats:italic>\n                  mice showed greater membrane stability than\n                  <jats:italic>mdx<\/jats:italic>\n                  hearts alone with intact\n                  <jats:italic>Actb<\/jats:italic>\n                  \/\n                  <jats:italic>Actg1<\/jats:italic>\n                  . We also observed that\n                  <jats:italic>\n                    Actb\/g1\n                    <jats:sup>fl\/fl-Myh6-Cre<\/jats:sup>\n                  <\/jats:italic>\n                  mice subjected to chronic pressure overload by transverse aortic constriction (TAC) were protected and developed less cardiac hypertrophy, had better preserved systolic function, and improved survival. Together, these data indicate induction of the cytoplasmic \u03b2-actin\/\u03b3-actin network in the heart during disease stimulation is maladaptive and weakens the sarcolemma, and 2 downstream mechanisms are considered that could mediate this effect.\n                <\/jats:p>","DOI":"10.64898\/2026.07.24.740593","type":"posted-content","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T13:55:28Z","timestamp":1785160528000},"source":"Crossref","is-referenced-by-count":0,"title":["Deletion of cytoplasmic \u03b2\/\u03b3-actin in the mouse heart protects from disease by augmenting sarcolemma stability"],"prefix":"10.64898","author":[{"given":"Yasuhide","family":"Kuwabara","sequence":"first","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-3039, USA"},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, 240 Albert Sabin Way, Cincinnati, OH, 45229-3039, USA"},{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaracho, Sakyo, Kyoto, 606-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin","family":"Keezer","sequence":"additional","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-3039, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eaman","family":"Abay","sequence":"additional","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-3039, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suh-Chin J.","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-3039, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3558-6529","authenticated-orcid":false,"given":"Jeffery D.","family":"Molkentin","sequence":"additional","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229-3039, USA"},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, 240 Albert Sabin Way, Cincinnati, OH, 45229-3039, 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