Sorbs2 Deficiency Causes Diastolic Dysfunction Through Dysregulation of Cytoskeletal Networks and Calcium Handling

Sorbin and SH3 domain–containing protein 2 (Sorbs2) is a cytoskeletal adaptor protein implicated in cardiomyocyte adhesion, cytoskeletal remodeling, and calcium handling. We investigated its role in diastolic dysfunction using Sorbs2 knockout (KO) mice. Sorbs2 KO mice developed progressive diastolic dysfunction with preserved systolic function, accompanied by left atrial enlargement, pulmonary edema, myocardial fibrosis, increased microtubule detyrosination, and impaired calcium handling. Bulk RNA-seq was performed on ventricular myocardium from wild-type (WT) and KO mice at 6 weeks and 6 months of age, with additional rescue experiments using AAV9-mediated re-expression of Sorbs2. RNA-seq revealed activation of extracellular matrix pathways and integrin signaling in KO mice, while mitochondrial metabolic pathways were downregulated. These data establish Sorbs2 as a critical regulator of diastolic function.