title: Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis.
abstract: Homozygous cardiac myosin binding protein C-deficient (Mybpc(t/t)) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold. We have investigated the mechanism of cardiac enlargement in these hearts. Throughout embryogenesis myocytes undergo cell division while maintaining the capacity to pump blood by rapidly disassembling and reforming myofibrillar components of the sarcomere throughout cell cycle progression. Shortly after birth, myocyte cell division ceases. Cardiac MYBPC is a thick filament protein that regulates sarcomere organization and rigidity. We demonstrate that many Mybpc(t/t) myocytes undergo an additional round of cell division within 10 d postbirth compared with their wild-type counterparts, leading to increased numbers of mononuclear myocytes. Short-hairpin RNA knockdown of Mybpc3 mRNA in wild-type mice similarly extended the postnatal window of myocyte proliferation. However, adult Mybpc(t/t) myocytes are unable to fully regenerate the myocardium after injury. MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression. We suggest that human patients with homozygous MYBPC3-null mutations develop dilated cardiomyopathy, coupled with myocyte hyperplasia (increased cell number), as observed in Mybpc(t/t) mice. Human patients, with heterozygous truncating MYBPC3 mutations, like mice with similar mutations, have hypertrophic cardiomyopathy. However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3(+/-) individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3(-/-) mice is primarily myocyte hyperplasia.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; Department of Biochemistry and Cardiovascular Research Institute, Yong Loo School of Medicine, National University of Singapore, Singapore 117599;
authors.forename: Jianming
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115; University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada;
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Burgon
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115; Department of Cardiology, Children's Hospital Boston, Boston, MA 02115;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115;
authors.forename: Kenji
authors.initials: K
authors.lastname: Onoue
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115;
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Gorham
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Caitlin C
authors.initials: CC
authors.lastname: O'Meara
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Gregory
authors.initials: G
authors.lastname: Fomovsky
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Texas Medical Center, Houston, TX 77204.
authors.forename: Bradley K
authors.initials: BK
authors.lastname: McConnell
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115; seidman@genetics.med.harvard.edu.
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D064127:Aurora Kinases / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002452:Cell Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D048749:Cytokinesis; D000229:Dependovirus / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D000099163:Myosin Binding Protein C
chemical_list: D064127:Aurora Kinases; D015415:Biomarkers; D002118:Calcium; D002352:Carrier Proteins; D006657:Histones; D007211:Indoles; D034741:RNA, Small Interfering; D000099163:Myosin Binding Protein C; C007293:DAPI
keywords: cardiac dilation; cardiac hypertrophy; cytokinesis; hyperplasia; myosin binding protein C