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Here, we show that SORBS2 is a vital component of murine cardiomyocyte adhesion complexes. Its genetic ablation in mice causes progressive diastolic dysfunction with preserved systolic function, accompanied by atrial enlargement and reduced survival. Postnatal cardiomyocyte-directed re-expression of SORBS2 restores diastolic indices and significantly improves longevity. Mechanistically, SORBS2 functions as an integrative scaffold linking adhesome integrity, cytoskeletal remodeling, and calcium homeostasis. SORBS2 deficiency increases microtubule detyrosination, reduces SERCA2 abundance, disrupts dyad-associated organization, which collectively impair active cardiomyocyte relaxation. Concurrently, this deficiency promotes extracellular matrix remodeling and myocardial fibrosis, driving passive ventricular stiffness. Pharmacological inhibition of microtubule detyrosination partially rescues relaxation defects. These findings establish SORBS2 as a key regulator of diastolic function and define a structural axis governing myocardial mechanics, offering potential therapeutic targets.<\/jats:p>","DOI":"10.1038\/s42003-026-10503-6","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T18:36:16Z","timestamp":1781721376000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SORBS2 regulates diastolic function through cytoskeletal networks and calcium handling"],"prefix":"10.1038","volume":"9","author":[{"given":"Zexuan","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0593-2277","authenticated-orcid":false,"given":"Camille","family":"Blandin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0550-2195","authenticated-orcid":false,"given":"Jiehui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael M.","family":"Peters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5366-881X","authenticated-orcid":false,"given":"Anna","family":"Ponek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dogacan","family":"Yucel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin Kit","family":"Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3605-3924","authenticated-orcid":false,"given":"Fujian","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4551-8079","authenticated-orcid":false,"given":"William T.","family":"Pu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"10503_CR1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.hfc.2007.10.007","volume":"4","author":"M Periasamy","year":"2008","unstructured":"Periasamy, M. & Janssen, P. 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