Cardiac-specific Deletion of GSK-3α and GSK-3β Leads to Fatal Dilated Cardiomyopathy With Mitotic Catastrophe

Abstract

In mammals, glycogen synthase kinase-3 (GSK-3) exists as two homologs, GSK-3α and GSK-3β, encoded by independent genes which share similar kinase domains but differ substantially in their N and C termini. Previously we have shown that cardiomyocyte specific deletion of 2 functional GSK-3α or 2 functional GSK-3β alleles has a negligible role in normal homeostasis of myocardial biology. In contrast, herein we describe the creation of mice that are specifically targeted to lack 3 or 4 GSK-3 alleles. Mice lacking any 3 of the alleles live longer than 120 days but develop cardiac hypertrophy and display impaired cardiac function assessed by hemodynamics. Mice lacking all four alleles (double knockout, DKO) develop profound dilated cardiomyopathy and heart failure, leading to death. Pathologically, the hearts of DKOs show giant myocardial nuclei, multi-nucleation, metabolic abnormalities including excess glycogen deposition, degeneration and cell death; and fibrotic remodeling. Microarray and functional pathway analysis demonstrate that these disturbances arise from marked disorders of the cell cycle. Western blot and immunofluorescence confocal microscopy show dysregulated expression of major cell cycle/checkpoint markers, apoptotic proteins and DNA damage markers. These findings indicate that the cardiomyocyte undergoes cell cycle initiation, but this is followed by mitotic catastrophy, DNA damage and apoptosis. This study confirms that GSK-3 is a central regulator of the cell cycle in the heart. Keywords: Mammals, Genes, Cardiomyocyte, Myocardial biology.