{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T10:36:45Z","timestamp":1791283005227,"version":"4.1.0"},"reference-count":78,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"13","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2022,7,5]]},"abstract":"<jats:sec xml:lang=\"en\"><jats:title>Background<\/jats:title><jats:p xml:lang=\"en\">Sorbin and SH3 domain containing 2 (Sorbs2) protein is a cytoskeletal adaptor with an emerging role in cardiac biology and disease; yet, its potential relevance to adult\u2010onset cardiomyopathies remains underexplored. Sorbs2 global knockout mice display lethal arrhythmogenic cardiomyopathy; however, the causative mechanisms remain unclear. Herein, we examine Sorbs2 dysregulation in heart failure, characterize novel Sorbs2 cardiomyocyte\u2010specific knockout mice (Sorbs2\u2010cKO), and explore associations between Sorbs2 genetic variations and human cardiovascular disease.<\/jats:p><\/jats:sec><jats:sec xml:lang=\"en\"><jats:title>Methods and Results<\/jats:title><jats:p xml:lang=\"en\">Bioinformatic analyses show myocardial Sorbs2 mRNA is consistently upregulated in humans with adult\u2010onset cardiomyopathies and in heart failure models. We generated Sorbs2\u2010cKO mice and report that they develop progressive systolic dysfunction and enlarged cardiac chambers, and they die with congestive heart failure at about 1\u00a0year old. After 3 months, Sorbs2\u2010cKO mice begin to show atrial enlargement and P\u2010wave anomalies, without dysregulation of action potential\u2013associated ion channel and gap junction protein expressions. After 6 months, Sorbs2\u2010cKO mice exhibit impaired contractility in dobutamine\u2010treated hearts and skinned myofibers, without dysregulation of contractile protein expressions. From our comprehensive survey of potential mechanisms, we found that within 4\u00a0months, Sorbs2\u2010cKO hearts have defective microtubule polymerization and compensatory upregulation of structural cytoskeletal and adapter proteins, suggesting that this early intracellular structural remodeling is responsible for contractile dysfunction. Finally, we identified genetic variants that associate with decreased Sorbs2 expression and human cardiac phenotypes, including conduction abnormalities, atrial enlargement, and dilated cardiomyopathy, consistent with Sorbs2\u2010cKO mice phenotypes.<\/jats:p><\/jats:sec><jats:sec xml:lang=\"en\"><jats:title>Conclusions<\/jats:title><jats:p xml:lang=\"en\">Our studies show that Sorbs2 is essential for maintaining structural integrity in cardiomyocytes, likely through strengthening the interactions between microtubules and other cytoskeletal proteins at cross\u2010link sites.<\/jats:p><\/jats:sec>","DOI":"10.1161\/jaha.122.025687","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T10:32:41Z","timestamp":1655893961000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in 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