Glucocorticoid Receptor ablation promotes cardiac regeneration by hampering cardiomyocyte terminal differentiation

Abstract

In mammals, glucocorticoid levels rise dramatically shortly before birth and prepare the foetus for post-natal life by promoting the maturation of the lungs and other organs. However, their impact on cardiac postnatal growth and regenerative plasticity is unknown. Here, we demonstrate that exposure to endogenous glucocorticoids facilitates cell cycle exit and reduces the proliferation of neonatal cardiomyocytes. This cytostatic activity is shared by several synthetic glucocorticoid receptor (GR) agonists routinely used in clinical settings. We also observed that GR levels increase in cardiomyocytes during early post-natal development. Importantly, in vivo cardiomyocyte-specific GR ablation delayed the transition from hyperplastic (increase in cell number) to hypertrophic (increase in cell size) growth. Further, GR ablation partially impaired cardiomyocyte maturation, reducing myofibrils-mitochondria organization along with the expression of genes involved in fatty acid metabolism, mitochondrial respiration and energy transfer from mitochondria to the cytosol. Finally, we show increased cardiomyocyte proliferation in GR ablated juvenile and adult cardiomyocytes in response to myocardial infarction in vivo, thus promoting cardiac tissue regeneration. We suggest that GR antagonization could serve as a strategy for heart regeneration based on endogenous cardiomyocyte renewal.