title: Postnatal telomere dysfunction induces cardiomyocyte cell-cycle arrest through p21 activation.
abstract: The molecular mechanisms that drive mammalian cardiomyocytes out of the cell cycle soon after birth remain largely unknown. Here, we identify telomere dysfunction as a critical physiological signal for cardiomyocyte cell-cycle arrest. We show that telomerase activity and cardiomyocyte telomere length decrease sharply in wild-type mouse hearts after birth, resulting in cardiomyocytes with dysfunctional telomeres and anaphase bridges and positive for the cell-cycle arrest protein p21. We further show that premature telomere dysfunction pushes cardiomyocytes out of the cell cycle. Cardiomyocytes from telomerase-deficient mice with dysfunctional telomeres (G3 Terc(-/-)) show precocious development of anaphase-bridge formation, p21 up-regulation, and binucleation. In line with these findings, the cardiomyocyte proliferative response after cardiac injury was lost in G3 Terc(-/-) newborns but rescued in G3 Terc(-/-)/p21(-/-) mice. These results reveal telomere dysfunction as a crucial signal for cardiomyocyte cell-cycle arrest after birth and suggest interventions to augment the regeneration capacity of mammalian hearts.
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Aix
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain.
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Gutiérrez-Gutiérrez
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain.
authors.forename: Carlota
authors.initials: C
authors.lastname: Sánchez-Ferrer
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: Aguado
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain iflores@cnic.es.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Flores
mesh_terms: D000705:Anaphase; D000818:Animals; D000831:Animals, Newborn; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D059505:Telomere Homeostasis
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D019098:Telomerase