Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis

Author:

Nakano Haruko1ORCID,Minami Itsunari2,Braas Daniel3,Pappoe Herman1,Wu Xiuju4,Sagadevan Addelynn1,Vergnes Laurent5,Fu Kai1,Morselli Marco1,Dunham Christopher6,Ding Xueqin6,Stieg Adam Z78ORCID,Gimzewski James K6789,Pellegrini Matteo1910ORCID,Clark Peter M3911,Reue Karen510,Lusis Aldons J451012,Ribalet Bernard13,Kurdistani Siavash K9101415,Christofk Heather3101415,Nakatsuji Norio216,Nakano Atsushi191015ORCID

Affiliation:

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.

Funder

Oppenheimer Foundation

University of California, Los Angeles

National Institute of Arthritis and Musculoskeletal and Skin Diseases

National Center for Research Resources

National Institutes of Health

Hunan University

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

Reference53 articles.

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