Metabolic reprogramming enhances oxidative stress resistance in differentiating cardiomyocytes.

Cardiomyocyte differentiation is a complex process involving significant metabolic remodeling, but its impact on cellular redox state and cell damage remains poorly understood. Using metabolomics, biophysical, and biochemical approaches, we characterized, in vitro, the metabolic shift of differentiating cardiomyocytes and its implications for oxidative damage. We found that differentiating cardiomyocytes undergo a broad metabolic reprogramming from a glycolytic to an oxidative state, marked by increased activity in key pathways, including malate-aspartate shuttle, glutathione metabolism, and tricarboxylic acid cycle. This metabolic transition was associated with mitochondrial enlargement and increased reactive oxygen species (ROS) production. Intriguingly, despite ROS increase, differentiated cells maintained similar levels of DNA damage as cardiomyoblasts and were more resistant to a H₂O₂ challenge. Our findings suggest that metabolic adaptations during cardiomyocyte differentiation enhance their capacity to mitigate oxidative stress damage, providing an adaptive avenue that enables cardiomyocyte survival upon exposure to an oxygen-rich environment.