Reductions in complex and hybrid N‐glycosylation are sufficient to cause dilated cardiomyopathy that deteriorates into heart failure through acute and chronic mechanisms

Dilated cardiomyopathy (DCM) is the third most common cause of heart failure (HF). Often, the responsible mechanisms are not fully understood, including whether the frequently associated arrhythmias contribute to DCM onset. A growing number of cardiac diseases, including cardiomyopathies, can present concurrently with modest changes in protein glycosylation; however, it is not known whether such altered glycosylation is pathogenic or subsequent to disease onset. Without availability and use of appropriate models, mechanistic evidence linking altered glycosylation to heart disease remains largely circumstantial. We recently created and characterized such a DCM model through the cardiomyocyte‐specific and late‐embryonic knockout of the glycosyltransferase, Mgat1 (Mgat1KO), whose expression was shown to be altered in human end‐stage idiopathic dilated cardiomyopathy. We demonstrated that all Mgat1KO mice present with DCM, HF, and early death. It was shown that the voltage‐gated Ca 2+ channel (Ca v ) α2δ1 subunit is a direct target of the glycosyltransferase encoded by Mgat1, with the less glycosylated α2δ1 subunits leading to altered Ca v gating. Additionally, voltage‐gated K+ channel (K v ) activity was significantly reduced through indirect mechanisms likely as a result of the progression of heart failure. Together, these phenomena led to changes in Ca 2+ handling, ec‐coupling, contraction and were pro‐arrhythmic (Ednie et al, FASEB J., 2019; Ednie et al, JMCC, 2019). To distinguish among the direct and disease‐related mechanisms by which reduced complex/hybrid N‐glycosylation cause DCM, here we created and initially characterized a second DCM model ‐ the cardiomyocyte‐specific knockout of Mgat1 induced in adult mice (Mgat1KO i ). Data show that Mgat1KO i cardiac contractility, reflected by measuring ejection fraction (EF), through 5 weeks post‐induction, is unchanged from pre‐induction EF. However, by 8 weeks post‐induction, the EF was significantly reduced and continued to decline. These data suggest that the Mgat1KO i model can be used up to 5 weeks post‐induction to determine acute and direct mechanisms ‐ at 8 weeks post‐induction, studies to determine disease‐related mechanisms can commence. Thus, cellular data collected at 3–5 weeks post‐induction demonstrate direct depolarizing shifts in myocyte Ca v gating similar to that reported for the chronic Mgat1KO, but with no measurable effects on K v activity. In summary, the constitutive Mgat1KO DCM model allows one to determine the clinical effects of reduced complex N‐glycosylation on cardiac function that result in arrhythmogenic DCM/HF, while the Mgat1KO i DCM model can be used to determine mechanisms by which direct alterations in the function of ec‐coupling‐related proteins such as Ca v , and disease‐related indirect effects such as on Kv activity or contractility, contribute to heart disease onset and progression. Support or Funding Information Supported in part by grants from the National Science Foundation [IOS‐1146882, IOS‐1660926, and MCB‐1856199; E.S.B.]; an American Heart Association Grant‐In‐Aid [14GRNT20450148; E.S.B.] and Postdoctoral Fellowship [15POST25710010; A.R.E.].