Knockout of Sorbs2 in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice

Rationale Sorbs2 is a cardiomyocyte-enriched, cytoskeletal adaptor protein, and given some evidence for its dysregulated expression in failing hearts, there is growing interest in understanding its roles in cardiac biology and disease. While Sorbs2 global knockout mice display lethal cardiomyopathy with severe arrhythmias, the underlying mechanisms remain unclear, and whether this results from intrinsic loss of Sorbs2 in cardiomyocytes is unknown, as Sorbs2 is also well-expressed in the nervous system and vasculature. In addition, the potential relevance of Sorbs2 in human cardiomyopathy remains underexplored. Objective To characterize the effects and potential underlying mechanisms of cardiomyocyte- specific deletion of Sorbs2 on cardiac structure and function in mice, and to further examine Sorbs2 dysregulation in failing hearts and explore potential links between Sorbs2 genetic variations and human cardiovascular disease phenotypes. Methods and Results We report that myocardial Sorbs2 expression is consistently upregulated in humans with ischemic and idiopathic cardiomyopathies, and in experimental animal models of heart failure (HF). We generated mice with cardiomyocyte-specific loss of Sorbs2 (Sorbs2-cKO) and found early atrial and ventricular conduction abnormalities, despite unaltered expression of primary action potential ion channels and gap junction proteins. At mid-life, Sorbs2-cKO mice exhibit impaired cardiac contractility with cardiomyofibers failing to maintain adequate mechanical tension. As a result, these mice develop progressive diastolic and systolic dysfunction, enlarged cardiac chambers, and die with congestive HF at approximately one year of age. Comprehensive survey of potential underlying mechanisms revealed that Sorbs2-cKO hearts exhibit defective microtubule polymerization and compensatory upregulation of structural proteins desmin, vinculin, and tubulins. Finally, consistent with our observations in mice, we identified suggestive links between Sorbs2 genetic variants and related human cardiac phenotypes, including conduction abnormalities, atrial enlargement, and dilated cardiomyopathy. Conclusions Our studies show that Sorbs2 is essential for maintaining cytoskeletal structural integrity in cardiomyocytes likely through strengthening the interactions between microtubules and other structural proteins at crosslink sites. Overall, this study provides key insights into the critical role for Sorbs2 in cardiomyocytes and likely other cell types in maintaining normal cardiac structure and function and highlights its potential clinical relevance. ### Competing Interest Statement The authors have declared no competing interest.