Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis

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.

Glucose metabolism promotes neonatal heart regeneration

“…In our previous study, we found that the nucleotide biosynthesis supported by the PPP is a key mechanism balancing cell proliferation and maturation during the physiological growth of cardiomyocytes. The balance between proliferation and maturation was successfully manipulated by addition of glucose or nucleotides (gain-of-function) and inhibition of the PPP and nucleotide biosynthesis (loss-of-function) in the in vitro settings 9 . The current study demonstrates that similar intervention may be effective during the neonatal stages to accelerate regeneration.…”

“…However, despite the established association between hyperglycemia and the heart malformation, little is known about how glucose impacts cardiomyocyte formation and reformation [30][31][32] . We have recently found that glucose induces cardiomyocyte proliferation at the sacrifice of its maturity via the pentose phosphate pathway and nucleotide biosynthesis during physiological heart formation 9 . The current study is the first to demonstrate that glucose metabolism is a critical determinant of cardiac regenerative capacity in vivo.…”

“…Our previous report found that glucose inhibits the cardiac maturation and promotes proliferation via the nucleotide biosynthesis during fetal development 9 . To test whether nucleotide biosynthesis also plays a central role in the glucose-induced cardiomyocyte regeneration, the neonatal hearts were injured in the presence of hydroxyurea (HU).…”

“…HU injections were performed 4 hours prior to cryoinjury and daily for 7 days. Edu was injected 4 hours prior to tissue harvest, hearts were dissociated to single cells at P7 as previously described 9,34 . The cells were stained for MitoTracker Orange CMTMRos (ThermoFisher), and further fixed and strained with Tnnt2 antibody (rabbit, 1:200, Sigma-Aldrich) and ClickIT EdU kit.…”

“…This timing is long before the metabolic switch from glucose to fatty acid after birth. We have previously found that the anabolic biosynthesis of building blocks from glucose, but not the catabolic extraction of energy, is a key regulator of cardiac maturation during late embryogenesis, raising an intriguing possibility that glucose is not merely to meet the energy demand but to drive the genetic program of cardiac maturation 9 .…”