Vitamin C Supplementation Mitigates Diabetes-Associated Skeletal Muscle Atrophy

Abstract Background Skeletal muscle atrophy is a major complication of diabetes linked with poor prognosis and reduced quality of life. Antioxidant vitamin C has shown promise in alleviating diabetic complications in rodents and mammals. Whether vitamin C is effective in mitigating diabetic muscle atrophy and the underlying molecular mechanisms remains unclear. The Drosophila larval body wall muscle offers a powerful system to identify interventions that target muscle atrophy and hypertrophy. Methods To induce diabetic conditions, wild-type Canton-S Drosophila larvae were fed with High Sugar Diet (HSD) with a final concentration of 1 M sucrose. Control larvae (CT) were fed a diet containing 0.1 M sucrose. Body wall muscles of mid-third instar larvae were used for molecular analysis. The effect of vitamin C on skeletal muscle regeneration was assessed using a streptozotocin-induced diabetic mouse model. Results HSD-fed larvae exhibited severe growth inhibition and developed hyperglycemia, accompanied by increased triglycerides in the hemolymph. Ventral longitudinal VL3 and VL4 body wall myofibers were reduced in size, exhibited decreased expression of mef2 and mhc, along with increased expression of FOXO target genes, indicating muscle atrophy. Supplementation of Vitamin C (Ascorbic acid) to HSD (HSD + AA) rescued growth inhibition, reduced food aversion, and alleviated diabetic phenotypes. Transcriptomic analysis of HSD + AA larval muscles revealed enhanced expression of genes linked to metabolism, muscle development, and differentiation. Vitamin C reduced oxidative stress and, interestingly, rescued the expression of epigenetic regulator Ten-eleven-translocation (Tet), which utilizes vitamin C as a cofactor for its activity. Furthermore, vitamin C improved skeletal muscle regeneration in the injured diabetic mice. Conclusion Collectively, our data demonstrate that vitamin C mitigates muscle atrophy and enhances skeletal muscle regeneration in diabetic muscles. These results suggest that vitamin C intake, in combination with anti-diabetic medications, may offer promising strategy to mitigate long-term diabetic complications.