Evidence for Neurohormonal Triggers of Cardiomyocyte Polyploidization and Cardiac Regenerative Potential Loss During Endothermy Acquisition

Tissue regenerative potential displays striking divergence across phylogeny and ontogeny, but the underlying mechanisms remain enigmatic. Loss of mammalian cardiac regenerative potential correlates with cardiomyocyte cell‐cycle arrest and polyploidization as well as the development of postnatal endothermy. Genetic evidences in both mice and zebrafish support that cardiomyocyte polyploidization represents a major barrier limiting cardiac regenerative capacity. Through phylogenetic analyses of 41 vertebrate species, we uncover that certain monotreme, edentate, cetacean, chiropteran species have unusually high percentages of diploid cardiomyocytes in the adult heart. Furthermore, diploid cardiomyocyte abundance conforms to Kleiber’s law—the 3/4‐power law scaling of metabolism with bodyweight—and inversely correlates with standard metabolic rate, body temperature, and serum thyroxine level. Inactivation of thyroid hormone signaling reduces mouse cardiomyocyte polyploidization, delays cell‐cycle exit, and retains cardiac regenerative potential in adults. Conversely, exogenous thyroid hormones inhibit zebrafish heart regeneration. Notably, inhibition of thyroid hormone synthesis in mice after birth results in low body temperatures. Recently, we discover the nervous system as a secondary major regulator of mammalian cardiomyocyte polyploidization, cell cycle arrest, and body temperature increase. Moreover, inhibitions of neuronal activity and thyroid hormone signaling in neonates have additive effects, yielding mice with the highest percentage of diploid cardiomyocytes and lowest body temperature to our knowledge. Thus, our results support a model where loss of cardiomyocyte regenerative capacity, driven by increasing neurohormonal activities, may be a tradeoff for the acquisition of endothermy during animal evolution and postnatal development. Support or Funding Information NIH