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  3. Maternal hyperglycemia disrupts cardiomyocyte maturation via aberrant nucleotide metabolism and suppression of AMPK signaling

Maternal hyperglycemia disrupts cardiomyocyte maturation via aberrant nucleotide metabolism and suppression of AMPK signaling

  • Cell Rep. 2026 May 26;45(5):117321. doi: 10.1016/j.celrep.2026.117321.
Haruko Nakano 1,  Naofumi Kawahira 1,  Alexander Vesprey 1,  Atsushi Nakano 2
Affiliations

Affiliations

  • 1 Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.
  • 2 Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA; University of California, Los Angeles, David Geffen Department of Medicine, Division of Cardiology, Los Angeles, CA, USA; The Jikei University School of Medicine, Department of Molecular Physiology, Tokyo, Japan; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: [email protected].
PMID: 42090289 DOI: 10.1016/j.celrep.2026.117321
Abstract

Glucose serves not only as an energy source but also as a signaling molecule for organ growth. Intrauterine hyperglycemia elevates the risk of congenital heart defects independently of genetic factors, although its underlying mechanisms remain unclear. In this study, we investigated the impact of maternal hyperglycemia on cardiac development using a diabetic pregnancy mouse model and pluripotent stem cell-derived cardiomyocytes. Multi-modal analysis revealed that hyperglycemia disrupts mitochondrial structure and function in fetal hearts even before overt malformations appear, indicating that mitochondrial immaturity is an early signature of diabetic embryopathy. Metabolomic profiling revealed nucleotide imbalance and subsequent AMP-activated protein kinase (AMPK) suppression-contrasting with reports of increased AMPK activity observed in hyperglycemic neural tube defects. Notably, pharmacological activation of AMPK restored cardiomyocyte and mitochondrial function under high-glucose conditions in vitro. Our findings demonstrate that high glucose inhibits cardiomyocyte maturation through dysregulated nucleotide metabolism and AMPK suppression, advancing understanding of hyperglycemia-induced cardiac developmental defects.

Keywords

AMPK signaling; CP: metabolism; CP: molecular biology; cardiac maturation; cardiogenesis; diabetic embryopathy; hiPSC-derived cardiomyocytes; metabolism; mitochondrial dynamics; nucleotide metabolism.

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