Regulation of Cardiomyocyte Polyploidy and Multinucleation by CyclinG1

Abstract

Rationale : Polyploidy and multinucleation are characteristic features of mammalian cardiomyocytes, which develop shortly after birth when most differentiated cardiomyocytes become acytokinetic. Cardiac overload and hypertrophy further increase the degree of polyploidy of cardiomyocytes, suggesting a role in cell type–specific responses to physiological and pathological stimuli. Objective : We sought to study the function of cyclinG1 in the regulation of polyploidy and multinucleation in cardiomyocytes. Methods and Results : We found that expression of cyclinG1, a transcriptional target of p53, coincides with arrest of cardiomyocyte proliferation and onset of polyploidization. Overexpression of cyclinG1 promoted DNA synthesis but inhibited cytokinesis in neonatal cardiomyocytes leading to an enlarged population of binuclear cardiomyocytes. Reciprocally, inactivation of the cyclinG1 gene in mice lowered the degree of polyploidy and multinucleation in cardiomyocytes. Moreover, lack of cyclinG1 prevented the increase of polynucleated cardiomyocytes in response to pressure overload and hypertrophy. Conclusions : CyclinG1 is an important player for the regulation of polyploidy and multinucleation in cardiomyocytes probably by inhibition of apoptosis caused by checkpoint activation.