Abstract 18622: Prevention of Complex and Hybrid N Glycosylation Causes Dilated Cardiomyopathy

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Abstract

Protein glycosylation is an essential post-translational modification that affects a myriad of physiological processes. Humans with genetic defects in glycosylation often present with multi-system disorders including significant cardiac deficits. Acquired heart diseases and related risk factors have also been associated with aberrant glycosylation, highlighting its importance in cardiac function. In both cases the link between causation and corollary remains enigmatic. GlcNacT1, encoded by the Mgat1 gene, is necessary for the formation of hybrid and complex N-linked glycan structures making it an attractive target to investigate the role of glycosylation in cardiac pathogenesis. Here we created a cardiomyocyte-specific Mgat1 knock-out mouse (Mgat1KO) to explore the relationship between glycosylation and heart function. Mgat1KO mice die significantly younger than controls, with an average age of death of ~37 weeks with no animals surviving past 47 weeks and demonstrate chamber dilation and systolic dysfunction as characterized by reductions in ejection fraction and fractional shortening by 30 and 40% respectively. Mgat1KO mice present with severe interstitial cardiac fibrosis and increased expression of the heart failure biomarkers atrial and brain natriuretic peptide and beta myosin, all consistent with human dilated cardiomyopathy that deteriorates into heart failure. Cardiomyocytes from Mgat1KO mice also show aberrant Ca2+ handling and dyssynchronous contraction evidenced by significant variations in fractional shortening during rhythmic contraction. These observed phenomena demonstrate that deletion of Mgat1 in cardiomyocytes is sufficient to significantly impact cardiac function at the whole-heart and cellular levels that results in heart failure and premature death. We also show that Mgat1 expression and activity are variable among human hearts, suggesting that Mgat1/GlcNacT1 are dynamically regulated and potential targets for disease-related cardiac remodeling. Taken together, Mgat1/GlcNacT1 expression and function are indispensable to proper cardiac function and the Mgat1KO mouse provides the first model available to investigate the relationship between cardiomyocyte glycosylation and cardiac disease.

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