(P16-027-23) Erythritol Synthesis Is Elevated by Oxidative Stress in Muscle Myotubes

Objectives: Elevated circulating erythritol is a predictive biomarker of cardiometabolic disease development, and this polyol can be elevated up to 20 years before disease onset. Erythritol is synthesized through the pentose phosphate pathway (PPP) in humans and other mammals. In mice, we have observed that drinking a 30% sucrose solution elevates plasma, kidney, and skeletal muscle erythritol content. Sugar-induced erythritol synthesis in muscle is surprising: in healthy adult muscle, there is very little PPP activity. Understanding the role of erythritol production in skeletal muscle is important due to the strong contribution of muscle to glucose disposal/homeostasis. We hypothesized that skeletal muscle cells would respond to factors known to promote PPP flux with increased erythritol synthesis.

Methods: C2C12 mouse myoblasts were differentiated for 4 days to produce mature myotubes. Myotubes were exposed to culture media containing 5 mM (low) or 25 mM (high) glucose for 24 hrs. All other experiments were performed in 25 mM glucose media. Next, myotubes were exposed to 10uM menadione to generate reactive oxygen species (ROS). Finally, to determine the effect of inhibiting alternate glucose-disposal pathways on erythritol synthesis, myotubes were treated with 10uM sorbinil, a polyol pathway inhibitor. After glucose or drug treatment, erythritol was measured using GC-MS and normalized to total protein content. Results were analyzed using an unpaired t-test.

Results: We found that high glucose increased myotube erythritol synthesis by 40% (p < 0.01). Strikingly, exposure to menadione increased myotube erythritol synthesis by more than 3-fold (p < 0.0001). Inhibiting the polyol pathway (which can dispose of up to 30% of glucose) did not elevate erythritol synthesis.

Conclusions: Our findings demonstrate that mature myotubes synthesize erythritol and are responsive to glucose availability and oxidative stress. Surprisingly, oxidative stress promoted erythritol synthesis more strongly than glucose or the inhibition of a primary glucose disposal pathway. This indicates that a combination of ROS and abundant glucose may be required to elevate muscle erythritol synthesis, likely by upregulating the PPP.

Funding Sources: This was supported by the Education and Workforce Development Predoctoral Fellowship from the USDA National Institute of Food and Agriculture.