Reduced Myocyte Complex N-glycosylation Causes Dilated Cardiomyopathy
Document Type
Article
Publication Date
2019
Digital Object Identifier (DOI)
https://doi.org/10.1096/fj.201801057R
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 Mgatl 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 Ca2+ channel (Cav) subunit (α281) is a GlcNAcT1 target, and Mgat1KO Cav activity is shifted to more-depolarized membrane potentials. Consistently, Mgat1KO cardiomyocyte Ca2+ 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. FASEB J. 33, 1248–1261 (2019). www.fasebj.org
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
The FASEB Journal, v. 33, issue 1, p. 1248-1261
Scholar Commons Citation
Ednie, Andrew R.; Deng, Wei; Yip, Kay-Pong; and Bennett, Eric S., "Reduced Myocyte Complex N-glycosylation Causes Dilated Cardiomyopathy" (2019). Molecular Pharmacology & Physiology Faculty Publications. 70.
https://digitalcommons.usf.edu/mpp_facpub/70
