Reduced myocyte complex N‐glycosylation causes dilated cardiomyopathy

Abstract

Protein glycosylation is an essential posttranslational modification that affects a myriad of physiologic processes. Humans with genetic defects in glycosylation, which result in truncated glycans, often present with significant cardiac deficits. Acquired heart diseases and their associated risk factors were also linked to aberrant glycosylation, highlighting its importance in human cardiac disease. In both cases, the link between causation and corollary remains enigmatic. The glycosyltransferase gene, mannosyl (α-1,3-)-glycoprotein β-1,2- N-acetylglucosaminyltransferase (Mgat1), whose product, N-acetylglucosaminyltransferase 1 (GlcNAcT1) is necessary for the formation of hybrid and complex N-glycan structures in the medial Golgi, was shown to be at reduced levels in human end-stage cardiomyopathy, thus making Mgat1 an attractive target for investigating the role of hybrid/complex N-glycosylation in cardiac pathogenesis. Here, we created a cardiomyocyte-specific Mgat1 knockout (KO) mouse to establish a model useful in exploring the relationship between hybrid/complex N-glycosylation and cardiac function and disease. Biochemical and glycomic analyses showed that Mgat1KO cardiomyocytes produce predominately truncated N-glycan structures. All Mgat1KO mice died significantly younger than control mice and demonstrated chamber dilation and systolic dysfunction resembling human dilated cardiomyopathy (DCM). Data also indicate that a cardiomyocyte L-type voltage-gated Ca channel (Ca) subunit (α2δ1) is a GlcNAcT1 target, and Mgat1KO Ca activity is shifted to more-depolarized membrane potentials. Consistently, Mgat1KO cardiomyocyte Ca handling is altered and contraction is dyssynchronous compared with controls. The data demonstrate that reduced hybrid/complex N-glycosylation contributes to aberrant cardiac function at whole-heart and myocyte levels drawing a direct link between altered glycosylation and heart disease. Thus, the Mgat1KO provides a model for investigating the relationship between systemic reductions in glycosylation and cardiac disease, showing that clinically relevant changes in cardiomyocyte hybrid/complex N-glycosylation are sufficient to cause DCM and early death.-Ednie, A. R., Deng, W., Yip, K.-P., Bennett, E. S. Reduced myocyte complex N-glycosylation causes dilated cardiomyopathy.

Altered Glycosylation in the Aging Heart

“…Together with our data that Neu5Ac/Gc-Gal-GlcNAc decreases in 22month-old mice and our MS data showing a reduction of complex-type glycans carrying terminal neuraminic acid, this suggests that sialylation might be critical for heart function. Notably, the reduction of complex-type N-glycans in our MS analysis of aged murine hearts corresponds with findings for mannosyl (α-1,3-)-glycoprotein β-1,2-N-acetylglucosaminyltransferase (Mgat1) KO mice, which develop dilated cardiomyopathy (Ednie et al, 2019).…”

A mutation in mannose‐phosphate‐dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type I and dystroglycanopathy

“…HCM has been reported in PMM2‐CDG, ATP6V1A‐CDG, and ATP6V1E1‐CDG . Recent studies have shown that abnormal glycosylation, for example, abnormal sialylation or reduced hybrid/complex N‐glycosylation, is related to heart disease . However, future investigations are required to understand the clinical relevance of these findings.…”

“…19 Recent studies have shown that abnormal glycosylation, for example, abnormal sialylation or reduced hybrid/complex N-glycosylation, is related to heart disease. [19][20][21] However, future investigations are required to understand the clinical relevance of these findings. So far, DCM has been described in FKRP-CDG, FKTN-CDG, POMT1-CDG, POMT2-CDG, DOLK-CDG, DPM3-CDG, and PGM1-CDG.…”

Identifying functional metabolic shifts in heart failure with the integration of omics data and a heart-specific, genome-scale model

“…(Deng et al, 2016). Knockouts of other genes related to protein glycosylation have also been shown to alter ion signaling in cardiomyocytes (Ednie et al, 2019;Montpetit et al, 2009), resulting in cardiac abnormalities. Finally, a congenital genetic defect in Neu5Ac synthesis led to dilated cardiomyopathy, which was confirmed in a genetic knockout in zebrafish (Wen et al, 2018).…”