Sympathetic Nerve Activity Promotes Cardiomyocyte Cell-Cycle Arrest And Binucleation

Adult mammalian hearts typically have little capacity to regenerate after injuries such as myocardial infarction. In contrast, neonatal mice during the first week of life possess an incredible ability to regenerate their hearts, though this capacity is lost shortly after birth. The physiological triggers mediating this transition remains poorly understood. In this study, we demonstrate that sympathetic nerve activity promotes cardiomyocyte cell-cycle arrest and binucleation. In mice hearts lacking sympathetic nerve inputs, we observe increased mononucleated cardiomyocyte numbers and elevated cardiomyocyte proliferation. Additionally, increased cardiomyocyte mononucleation and proliferation are observed in mice with genetic and pharmacological inhibition of {beta}-adrenergic receptors ({beta}ARs), which mediate sympathetic nerve signaling. Using in vitro cultures of neonatal cardiomyocytes, we demonstrate that activation of {beta}-adrenergic receptors results in decreased cardiomyocyte proliferation that is mediated through cyclic AMP-dependent protein kinase (PKA) signaling. Taken together, these results suggest that sympathetic nerve activity may play a role in limiting the ability of mammalian hearts to regenerate by restricting cardiomyocyte proliferation and promoting cytokinesis failure leading to multinucleation.