Evidence for hormonal control of heart regenerative capacity during endothermy acquisition

The price of staying warm Among vertebrates, zebrafish and salamanders can regenerate their hearts, whereas adult mice and humans cannot. Hirose et al. analyzed diploid cardiomyocyte frequency as a proxy for cardiac regenerative potential across 41 vertebrate species (see the Perspective by Marchianò and Murry). They observed an inverse correlation of these cells with thyroid hormone concentrations during the ectotherm-to-endotherm transition. Mice with defects in thyroid hormone signaling retained significant heart regenerative capacity, whereas zebrafish exposed to excessive thyroid hormones exhibit impaired cardiac repair. Loss of heart regenerative ability in mammals may represent a trade-off for increases in metabolism necessary for the development of endothermy. Science, this issue p. 184; see also p. 123 Increasing thyroid hormone levels during the evolution and development of endothermy may limit heart regenerative potential. 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. We reveal that diploid cardiomyocyte abundance across 41 species conforms to Kleiber’s law—the ¾-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. Thus, our findings suggest that loss of heart regenerative capacity in adult mammals is triggered by increasing thyroid hormones and may be a trade-off for the acquisition of endothermy.