Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy

Abstract

Rationale Cardiac myocyte-specific deletion of either Glycogen Synthase Kinase (GSK)3A or GSK3B leads to cardiac protection following myocardial infarction, suggesting that deletion of both isoforms may provide synergistic protection. This is an important consideration due to the fact that all GSK-3–targeted drugs including the drugs already in clinical trial target both isoforms of GSK-3 and none are isoform specific. Objective To identify the consequences of combined deletion of cardiac myocyte GSK3A and GSK3B in heart function. Methods and Results We generated tamoxifen-inducible cardiac myocyte-specific mice lacking both GSK-3 isoforms (double knockout, DKO). We unexpectedly found that cardiac myocyte GSK-3 is essential for cardiac homeostasis and overall survival. Serial echocardiographic analysis reveals that within 2 weeks of tamoxifen treatment, DKO hearts leads to excessive dilatative remodeling and ventricular dysfunction. Further experimentation with isolated adult cardiac myocytes and fibroblasts from DKO implicated cardiac myocytes intrinsic factors responsible for observed phenotype. Mechanistically, loss of GSK-3 in adult cardiac myocytes resulted in induction of mitotic catastrophe, a previously unreported event in cardiac myocytes. DKO cardiac myocytes showed cell cycle progression resulting in increased DNA content and multi-nucleation. However, increased cell cycle activity was rivaled by marked activation of DNA damage, cell cycle checkpoint activation, and mitotic catastrophe induced apoptotic cell death. Importantly, mitotic catastrophe was also confirmed in isolated adult cardiac myocytes. Conclusion Together, our findings suggest that cardiac myocyte GSK-3 is required to maintain normal cardiac homeostasis and its loss is incompatible with life due to cell cycle dysregulation that ultimately results in a severe fatal dilated cardiomyopathy.

MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents

“…Interestingly, a significant increase in smaller mono-nucleated CMs was seen in miR-210 group, while the number of multi-nucleated CMs was reduced. This observation supports CM cell cycle re-entry resulting in proliferation, and reduced mitotic catastrophe-induced cell death as reported by earlier studies [36]. In continuation, we observed fourfold increment in EdU and Ki67 labeling in miR-210 transfected CMs as compared to control, while the cell number was almost double in miR-210 group.…”

Response by Zhou et al to Letter Regarding Article, “Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy”

“…Karlstaedt and Taegtmeyer for their favorable comments on our recent report demonstrating mitotic catastrophe as a key mechanism of fatal dilated cardiomyopathy in GSK-3 deficient hearts (conditional GSK-3α/β double knockout, DKO). 1 Considering the complex biology of GSK-3 in regulating numerous biological processes and cellular functions, we completely agree with Drs. Karlstaedt and Taegtmeyer that there may be additional layer(s) of complexity to be elucidated for the complete understanding of the molecular basis of the observed phenotype.…”

Sonodynamic Therapy Inhibits Fibrogenesis in Rat Cardiac Fibroblasts Induced by TGF-β1

“…Using neonatal rat cardiac fibroblasts, we further investigated the antifibrotic signaling of SDT and its interaction with the fibrotic signaling of TGF-β1. Many studies have indicated that GSK3β regulates the activities of several metabolic, signaling and structural proteins [25][26][27], and play an important role in CF activation and fibrotic remodeling after myocardial infarction [24]. Forde et al reported that GSK3β deletion leads to hyperactivation of profibrotic TGF-β1/SMAD3 signaling that is associated with excessive fibrosis and adverse ventricular remodeling [28].…”