Glycemia reprograms substrate transport and shapes divergent stress responses in differentiating H9c2 cells
Authors:Sofia Passaponti1, Asia Iserani2, Roberta Romagnoli2, Laura Cresti2, Cinzia Del Gaudio2, Alice Luddi3, Leonardo Ermini2 and Francesca Ietta2
1Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy. 2Department of Life Sciences, University of Siena, Siena, Italy. 3Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
Keywords:
glycemic stress, cardiac metabolism, fetal development, maternal malnutrition, pregnancy.
Corresponding Author(s):
Conflict of interest statement:
The authors declare no conflict of interest.
Please cite this article as:
Sofia Passaponti, Asia Iserani, Roberta Romagnoli, Laura Cresti, Cinzia Del Gaudio, Alice Luddi, Leonardo Ermini, Francesca Ietta (2026). Glycemia reprograms substrate transport and shapes divergent stress responses in differentiating H9c2 cells. Cell Stress 10: 74-87. doi: 10.15698/cst2026.10.321
© 2026 Passaponti et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
Metabolic stress is a major determinant of cell fate, particularly during differentiation, when long-lasting adaptations shape cellular responses to subsequent insults. Early-life glycemic instability is increasingly recognized as a stressor capable of programming cardiomyocyte metabolism and vulnerability, yet its direct impact on stress-response pathways during cardiomyocyte differentiation remains poorly defined. Here, we used differentiating H9c2 cardiomyoblasts to model chronic hypoglycemic (2.5 mM), normoglycemic (5 mM), and hyperglycemic (30 mM) conditions as opposing metabolic challenges, and examined their effects on substrate transport, lipid homeostasis, and stress-induced cell death pathways. Both hypoglycemic and hyperglycemic stress reprogrammed phenotypes, but through distinct mechanisms. Hypoglycemic stress increased expression of the glucose transporter GLUT1, concomitantly enhancing functional glucose uptake. It also upregulated the fatty-acid transporter CD36 and carnitine palmitoyltransferase-1 (CPT1), indicating coordinated enhancement of substrate uptake and mitochondrial fattyacid oxidation. In contrast, hyperglycemic stress suppressed GLUT1 expression and decreased glucose uptake, while increasing CD36 without upregulating CPT1. Under iso-osmotic conditions, this resulted in intracellular lipid accumulation consistent with an overload and lipotoxic stress. When challenged with anoxia–reoxygenation, hypoglycemiaconditioned cells predominantly engaged autophagy, as shown by increased LC3B-II/LC3B-I ratio, whereas hyperglycemia-conditioned cells exhibited enhanced apoptotic signaling, with increased caspase-3, PARP cleavage and DNA fragmentation. Notably, normoglycemic differentiation conferred the greatest resistance to oxygen fluctuations. Together, these findings demonstrate that chronic glycemic stress during cardiomyoblast differentiation programs divergent stress-response pathways, biasing cells toward autophagy or apoptosis in response to acute injury. This work highlights metabolic homeostasis as a critical determinant of cellular stress resilience and provides mechanistic insight into how early metabolic stress shapes cardiomyocyte vulnerability.