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The Role of GSK3β in SERCA Dysfunction and the Development of Arrhythmogenic Cardiomyopathy

The sarco(endo)plasmic reticulum Ca2+‐ATPase (SERCA) pump catalyzes the active transport of Ca2+ into the sarcoplasmic reticulum and is responsible for over 70% of Ca2+ turnover after muscle contraction. Phospholamban (PLN) is a well‐known SERCA regulator, and impaired SERCA function due to reductions in SERCA and/or enhanced inhibitory PLN action has been linked to the development of various cardiomyopathies. Arrhythmogenic cardiomyopathy (ACM) is an inherited, non‐ischemic heart disease presenting with ventricular arrhythmias, hypo/dyskinesia, and fibrotic remodeling. Over 60% of ACM cases are caused by pathogenic variants in genes encoding the cardiac desmosome, where Desmoglein‐2 (DSG2) is the second most prevalent desmosomal gene variant in the ACM patient population. Using Dsg2 mutant (Dsg2mut/mut) mice, previous studies showed that the enzyme glycogen synthase kinase‐3β (GSK3β), plays a major role in ACM pathogenesis. Inhibiting GSK3β in these mice improved cardiac contractility and ACM pathological phenotypes. We have shown that GSK3β inhibition in cardiomyocytes can also improve SERCA function in wild‐type (WT) mice; however, the role of GSK3β activity on SERCA function in Dsg2mut/mut mice is currently unknown.