C2C12 muscle myotubes, but not kidney proximal tubule HK-2 cells, elevate erythritol synthesis in response to oxidative stress

Abstract

BackgroundAs a biomarker, elevated serum erythritol predicts type 2 diabetes and cardiovascular disease onset. Erythritol was recently shown to be a product of human glucose metabolism through the pentose phosphate pathway. The regulation of erythritol synthesis from glucose has been explored in cancer cells, but not in non-transformed cells. ObjectiveThe kidneys and skeletal muscle have increased erythritol content in response to dietary sucrose, which suggests that they may significantly contribute to circulating erythritol levels. In the present study, we evaluated if conditions that promote erythritol synthesis in cancer cells are consistent in skeletal muscle and kidney cells. MethodsC2C12 myotubules were used as a model for skeletal muscle and HK-2 human proximal tubule cells were used to model kidney. C2C12 cells were exposed to high-or low-glucose conditions. Both C2C12 and HK-2 cells were exposed to the free radical generator menadione, then intracellular reactive oxygen species (ROS) and erythritol were measured. Intracellular sorbitol levels were also measured because increased polyol flux is also observed after exposure to excess glucose and oxidative stress. ResultsIntracellular erythritol was significantly elevated in C2C12 cells following both high glucose and menadione treatment. In contrast, HK-2 cells did not increase erythritol synthesis in response to oxidative stress. Generation of ROS through hydrogen peroxide (H2O2) exposure elevated sorbitol levels in both C2C12 and HK-2 cells, whereas generation of radicals with menadione treatment did not affect sorbitol production in either cell type. ConclusionsThese findings highlight that the factors contributing to elevated erythritol synthesis vary between cell types. More specifically, these studies demonstrate that muscle cells increase erythritol synthesis in response to both high glucose in culture medium and oxidative stress, whereas kidney cells increase erythritol synthesis only in response to high glucose.