Evidence for hormonal control of heart regenerative capacity during endothermy acquisition

Science. 2019 Apr 12;364(6436):184-188. doi: 10.1126/science.aar2038. Epub 2019 Mar 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Body Temperature Regulation
  • Cell Cycle Checkpoints
  • Cell Proliferation
  • Diploidy
  • Heart / physiology*
  • Mice
  • Myocytes, Cardiac / classification
  • Myocytes, Cardiac / physiology*
  • Phylogeny
  • Polyploidy*
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / physiology
  • Regeneration / drug effects
  • Regeneration / genetics
  • Regeneration / physiology*
  • Signal Transduction
  • Thyroid Hormones / pharmacology
  • Thyroid Hormones / physiology*
  • Zebrafish


  • Receptors, Thyroid Hormone
  • Thyroid Hormones