title: Developmental changes in the balance of glycolytic ATP production and oxidative phosphorylation in ventricular cells: A simulation study.
abstract: The developmental program of the heart requires accurate regulation to ensure continuous circulation and simultaneous cardiac morphogenesis, because any functional abnormalities may progress to congenital heart malformation. Notably, energy metabolism in fetal ventricular cells is regulated in a manner that differs from adult ventricular cells: fetal cardiomyocytes generally have immature mitochondria and fetal ventricular cells show greater dependence on glycolytic ATP production. However, although various characteristics of energy metabolism in fetal ventricular cells have been reported, to our knowledge, a quantitative description of the contributions of these factors to fetal ventricular cell functions has not yet been established. Here, we constructed a mathematical model to integrate various characteristics of fetal ventricular cells and predicted the contribution of each characteristic to the maintenance of intracellular ATP concentration and sarcomere contraction under anoxic conditions. Our simulation results demonstrated that higher glycogen content, higher hexokinase activity, and lower creatine concentration helped prolong the time for which ventricular cell contraction was maintained under anoxic conditions. The integrated model also enabled us to quantitatively assess the contributions of factors related to energy metabolism in ventricular cells. Because fetal cardiomyocytes exhibit similar energy metabolic profiles to stem cell-derived cardiomyocytes and those in the failing heart, an improved understanding of these fetal ventricular cells will contribute to a better comprehension of the processes in stem cell-derived cardiomyocytes or under pathological conditions.
authors.affiliation: Institute for Advanced Biosciences, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan; Department of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan. Electronic address: ducky@sfc.keio.ac.jp.
authors.forename: Hitomi I
authors.initials: HI
authors.lastname: Sano
authors.affiliation: Institute for Advanced Biosciences, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan; Systems Biology Program, Graduate School of Media and Governance, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan. Electronic address: toki@sfc.keio.ac.jp.
authors.forename: Tamami
authors.initials: T
authors.lastname: Toki
authors.affiliation: Institute for Advanced Biosciences, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan; Systems Biology Program, Graduate School of Media and Governance, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan; Department of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan. Electronic address: ynaito@sfc.keio.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Naito
authors.affiliation: Institute for Advanced Biosciences, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan; Systems Biology Program, Graduate School of Media and Governance, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan; Department of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan. Electronic address: mt@sfc.keio.ac.jp.
authors.forename: Masaru
authors.initials: M
authors.lastname: Tomita
mesh_terms: D000200:Action Potentials; D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D003198:Computer Simulation; D004734:Energy Metabolism; D005318:Fetal Heart / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D005311:Fetal Hypoxia; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D010085:Oxidative Phosphorylation; D012518:Sarcomeres / Q000378:metabolism
chemical_list: D000255:Adenosine Triphosphate; D006003:Glycogen; D006593:Hexokinase
keywords: Anoxia; Creatine; Glycogen; Mitochondria; Oxidative phosphorylation