Abstract P1034: Neurohormonal Pathways Drive Postnatal Thermogenesis And Loss Of Cardiac Regenerative Potential

Abstract

Why do mammalian organs including the heart lose regenerative potential during the perinatal window remains enigmatic. Through phylogenetic analysis of vertebrate cardiomyocyte ploidy as a proxy for cardiac regenerative potential, we uncover that certain monotreme, edentate, cetacean, chiropteran species have unusually high percentages of diploid cardiomyocytes in the adult heart. Cardiomyocyte abundance across 41 vertebrate species conforms to Kleiber's law, the 3/4-power law scaling of metabolism with bodyweight, and decreases when the standard metabolic rate and body temperature increase during the ectotherm-to-endotherm transition. Recently, following the fractal feature of the cardiovascular system, we further strengthen the link between endothermy and heart physiology. Thermogenesis increases by more than 10-fold during the ectotherm-to-endotherm transition requiring similar increases in blood flow and cardiac function that may impede heart regenerative potential. Moreover, we report sympathetic nerve-adrenergic receptor and thyroid hormone signaling as two major pathways promoting both thermogenesis and cardiomyocyte cell cycle arrest. Combined inhibition of postnatal adrenergic and thyroid hormone signaling results in juvenile mice with strikingly low body temperatures (~25 ° C), significantly elevated abundances of diploid cardiomyocytes (~60%), dramatically increased cardiomyocyte proliferation, and enhanced cardiac regenerative abilities when analyzed at postnatal day 14. Intriguingly, both neurohormonal pathways seem to be inactive in adult zebrafish hearts. Altogether, our findings support critical roles of two major thermogenic pathways in suppressing heart regenerative capacity, and implicate that the limited regenerative capacity in various adult mammalian tissues may be a tradeoff for the acquisition of endothermy in ontogeny and phylogeny.