title: Alterations in sarcomere function modify the hyperplastic to hypertrophic transition phase of mammalian cardiomyocyte development.
abstract: It remains unclear how perturbations in cardiomyocyte sarcomere function alter postnatal heart development. We utilized murine models that allowed manipulation of cardiac myosin-binding protein C (MYBPC3) expression at critical stages of cardiac ontogeny to study the response of the postnatal heart to disrupted sarcomere function. We discovered that the hyperplastic to hypertrophic transition phase of mammalian heart development was altered in mice lacking MYBPC3 and this was the critical period for subsequent development of cardiomyopathy. Specifically, MYBPC3-null hearts developed evidence of increased cardiomyocyte endoreplication, which was accompanied by enhanced expression of cell cycle stimulatory cyclins and increased phosphorylation of retinoblastoma protein. Interestingly, this response was self-limited at later developmental time points by an upregulation of the cyclin-dependent kinase inhibitor p21. These results provide valuable insights into how alterations in sarcomere protein function modify postnatal heart development and highlight the potential for targeting cell cycle regulatory pathways to counteract cardiomyopathic stimuli.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Nixon
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine.
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Williams
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Glennon
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine.
authors.forename: Alejandro E
authors.initials: AE
authors.lastname: de Feria
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Sebag
authors.affiliation: Department of Pediatrics, Division of Pediatric Cardiology.|Department of Cellular and Developmental Biology.
authors.forename: H Scott
authors.initials: HS
authors.lastname: Baldwin
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine.|Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Becker
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002453:Cell Cycle; D049108:Cell Enlargement; D049109:Cell Proliferation / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006321:Heart / Q000254:growth & development*; D006965:Hyperplasia; D006984:Hypertrophy; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism* / Q000502:physiology; D015854:Up-Regulation; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D000099163:Myosin Binding Protein C