eLife (Dec 2017)
Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis
- Haruko Nakano,
- Itsunari Minami,
- Daniel Braas,
- Herman Pappoe,
- Xiuju Wu,
- Addelynn Sagadevan,
- Laurent Vergnes,
- Kai Fu,
- Marco Morselli,
- Christopher Dunham,
- Xueqin Ding,
- Adam Z Stieg,
- James K Gimzewski,
- Matteo Pellegrini,
- Peter M Clark,
- Karen Reue,
- Aldons J Lusis,
- Bernard Ribalet,
- Siavash K Kurdistani,
- Heather Christofk,
- Norio Nakatsuji,
- Atsushi Nakano
Affiliations
- Haruko Nakano
- ORCiD
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- Itsunari Minami
- Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Japan
- Daniel Braas
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States
- Herman Pappoe
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- Xiuju Wu
- Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, United States
- Addelynn Sagadevan
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- Laurent Vergnes
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States
- Kai Fu
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- Marco Morselli
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- Christopher Dunham
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States
- Xueqin Ding
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States
- Adam Z Stieg
- ORCiD
- California NanoSystems Institute, University of California, Los Angeles, Los Angeles, United States; WPI Center for Materials Nanoarchitectonics (MANA), National Institute for Materials Science, Meguro, Japan
- James K Gimzewski
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, United States; WPI Center for Materials Nanoarchitectonics (MANA), National Institute for Materials Science, Meguro, Japan; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, United States
- Matteo Pellegrini
- ORCiD
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, United States; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, United States; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States
- Peter M Clark
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, United States; Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, United States
- Karen Reue
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States
- Aldons J Lusis
- Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, United States; Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States
- Bernard Ribalet
- Department of Physiology, University of California, Los Angeles, Los Angeles, United States
- Siavash K Kurdistani
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, United States; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, United States; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, United States
- Heather Christofk
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, United States; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, United States
- Norio Nakatsuji
- Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Japan; Institute for Life and Frontier Medical Sciences, Kyoto University, Kyoto, Japan
- Atsushi Nakano
- ORCiD
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, United States; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, United States; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, United States
- DOI
- https://doi.org/10.7554/eLife.29330
- Journal volume & issue
-
Vol. 6
Abstract
The heart switches its energy substrate from glucose to fatty acids at birth, and maternal hyperglycemia is associated with congenital heart disease. However, little is known about how blood glucose impacts heart formation. Using a chemically defined human pluripotent stem-cell-derived cardiomyocyte differentiation system, we found that high glucose inhibits the maturation of cardiomyocytes at genetic, structural, metabolic, electrophysiological, and biomechanical levels by promoting nucleotide biosynthesis through the pentose phosphate pathway. Blood glucose level in embryos is stable in utero during normal pregnancy, but glucose uptake by fetal cardiac tissue is drastically reduced in late gestational stages. In a murine model of diabetic pregnancy, fetal hearts showed cardiomyopathy with increased mitotic activity and decreased maturity. These data suggest that high glucose suppresses cardiac maturation, providing a possible mechanistic basis for congenital heart disease in diabetic pregnancy.
Keywords
