title: A proliferative burst during preadolescence establishes the final cardiomyocyte number.
abstract: It is widely believed that perinatal cardiomyocyte terminal differentiation blocks cytokinesis, thereby causing binucleation and limiting regenerative repair after injury. This suggests that heart growth should occur entirely by cardiomyocyte hypertrophy during preadolescence when, in mice, cardiac mass increases many-fold over a few weeks. Here, we show that a thyroid hormone surge activates the IGF-1/IGF-1-R/Akt pathway on postnatal day 15 and initiates a brief but intense proliferative burst of predominantly binuclear cardiomyocytes. This proliferation increases cardiomyocyte numbers by ~40%, causing a major disparity between heart and cardiomyocyte growth. Also, the response to cardiac injury at postnatal day 15 is intermediate between that observed at postnatal days 2 and 21, further suggesting persistence of cardiomyocyte proliferative capacity beyond the perinatal period. If replicated in humans, this may allow novel regenerative therapies for heart diseases.
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Nawazish
authors.initials: N
authors.lastname: Naqvi
authors.affiliation: Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA 30308, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Thor
authors.initials: T
authors.lastname: Tejada
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA 30308, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Lambert
authors.affiliation: Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kesteven
authors.affiliation: Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Holman
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Torahiro
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Lovelock
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Wesley W
authors.initials: WW
authors.lastname: Howard
authors.affiliation: Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; University of New South Wales, Kensington, NSW 2033, Australia.
authors.forename: Siiri E
authors.initials: SE
authors.lastname: Iismaa
authors.affiliation: Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
authors.forename: Andrea Y
authors.initials: AY
authors.lastname: Chan
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Center for Cardiovascular Biology, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Crawford
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Center for Cardiovascular Biology, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Wagner
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: David I K
authors.initials: DI
authors.lastname: Martin
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA 30308, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.affiliation: Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; University of New South Wales, Kensington, NSW 2033, Australia. Electronic address: b.graham@victorchang.edu.au.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Graham
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: ahusai2@emory.edu.
authors.forename: Ahsan
authors.initials: A
authors.lastname: Husain
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002469:Cell Separation; D006321:Heart / Q000254:growth & development*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: D014284:Triiodothyronine