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

doi:10.7554/eLife.29330

Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis

Elife. 2017 Dec 12:6:e29330. doi: 10.7554/eLife.29330.

Authors

Haruko Nakano¹, Itsunari Minami², Daniel Braas³, Herman Pappoe¹, Xiuju Wu⁴, Addelynn Sagadevan¹, Laurent Vergnes⁵, Kai Fu¹, Marco Morselli¹, Christopher Dunham⁶, Xueqin Ding⁶, Adam Z Stieg^{7

8}, James K Gimzewski^{6

7

8

9}, Matteo Pellegrini^{1

9

10}, Peter M Clark^{3

9

11}, Karen Reue^{5

10}, Aldons J Lusis^{4

5

10

12}, Bernard Ribalet¹³, Siavash K Kurdistani^{9

10

14

15}, Heather Christofk^{3

10

14

15}, Norio Nakatsuji^{2

16}, Atsushi Nakano^{1

9

10

15}

Affiliations

¹ Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
² Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Japan.
³ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States.
⁴ Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, United States.
⁵ Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States.
⁶ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States.
⁷ California NanoSystems Institute, University of California, Los Angeles, Los Angeles, United States.
⁸ WPI Center for Materials Nanoarchitectonics (MANA), National Institute for Materials Science, Meguro, Japan.
⁹ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, United States.
¹⁰ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States.
¹¹ Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, United States.
¹² Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States.
¹³ Department of Physiology, University of California, Los Angeles, Los Angeles, United States.
¹⁴ Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, United States.
¹⁵ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, United States.
¹⁶ Institute for Life and Frontier Medical Sciences, Kyoto University, Kyoto, Japan.

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: cardiac; developmental biology; diabetes; human; human pluripotent stem cell; mouse; stem cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / drug effects
Embryonic Stem Cells / cytology*
Embryonic Stem Cells / drug effects
Embryonic Stem Cells / metabolism
Female
Gene Expression Profiling
Glucose / pharmacology*
Humans
Mice
Mice, Inbred C57BL
Muscle Development / drug effects*
Myocardium / cytology*
Myocardium / metabolism
Myocytes, Cardiac / cytology*
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism
Nucleotides / biosynthesis*
Pentose Phosphate Pathway
Pregnancy
Sweetening Agents / pharmacology

Substances

Nucleotides
Sweetening Agents
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding