Abstract
In fetal life heart growth is driven by cardiac myocyte cell division, but soon after birth, these cells withdraw from the cell cycle and further heart grow takes place via cellular hypertrophy. Sympathetic innervation of the heart takes place concomitantly with this key developmental transition in myocytes. We therefore investigated whether sympathetic signaling regulates myocyte development using an in vitro culture system containing neonatal sympathetic neurons and cardiac myocytes. Our data showed a strong trend at 2 days in vitro, with myocytes cultured in the presence of sympathetic neurons showing higher rates of proliferation as compared to myocytes cultured alone. This suggests that sympathetic signaling increases the proliferative capacity of cardiac myocytes before they withdraw from the cell cycle. The molecular mechanisms that underlie this proliferative regulation were examined in an in vivo lesion model in which sympathetic innervation to the heart was ablated. The expression of three genes involved in myocyte cell cycle regulation, c-myc, Meis1, and ALMS1, were compared between 6-OHDA lesioned hearts and control hearts at P2, P7, and 8 weeks. C-myc showed decreased expression in P2 lesioned hearts as compared to age-matched control hearts. Meis1 showed an increase in expression in both P2 and P7 lesioned hearts as compared to controls. These two results suggest that sympathetic signaling may interact with c-myc and Meis1 at different points in development to regulate cardiac myocyte proliferation. ALMS1, however, showed no difference in expression between control and lesion hearts at P2 and P7, suggesting that ALMS1 may not interact with sympathetic signaling to regulate myocyte proliferation. Further experiments will uncover the specific role of Meis1 in the complex signaling pathway that underlies sympathetic regulation.