Vitamin C supplementation mitigates hyperglycemia-associated muscle atrophy-like phenotypes and improves skeletal muscle regeneration

Abstract

Skeletal muscle atrophy is a major complication associated with diabetes and hyperglycemia and contributes to poor prognosis and reduced quality of life. Vitamin C, an antioxidant, has shown beneficial effects against diabetic complications in rodents and other mammals. However, whether vitamin C can mitigate hyperglycemia-associated muscle atrophy and the underlying mechanisms remain unclear. The Drosophila larval body wall muscle provides a useful system for studying interventions that modulate muscle homeostasis. Hyperglycemic conditions were induced by feeding wild-type Canton-S Drosophila larvae a High Sugar Diet (HSD; 1 M sucrose) while control larvae received 0.15 M sucrose. Body wall muscles from wandering third-instar larvae were used for analysis. The effects of vitamin C were further evaluated in differentiating C2C12 myoblasts and streptozotocin (STZ)-induced hyperglycemic mice subjected to skeletal muscle injury. HSD-fed larvae exhibited growth inhibition, hyperglycemia, impaired insulin response, and increased triglyceride levels. Ventral longitudinal VL3 and VL4 myofibers were reduced in size and showed decreased expression of Myocyte Enhancer Factor 2 (MEF2) and Myosin Heavy Chain (MHC), along with increased expression of Drosophila Atrogin-1 homolog, CG11658, and Forkhead Box O (FOXO) target genes, consistent with a muscle atrophy-like phenotype. Vitamin C Supplementation partially rescued growth defects, improved food intake, and reduced several hyperglycemia-associated phenotypes. Transcriptomic analysis of larval muscles revealed enrichment of genes involved in metabolism, muscle development, and differentiation. Vitamin C reduced oxidative stress and restored the expression of the epigenetic regulator Ten-eleven-translocation (Tet). Furthermore, vitamin C enhanced myogenic differentiation under high sugar conditions and improved skeletal muscle regeneration in hyperglycemic mice. Vitamin C mitigates muscle atrophy-like phenotypes in hyperglycemic larvae, promotes myogenic differentiation under high-sugar conditions, and enhances skeletal muscle regeneration in hyperglycemic mice. These findings support further investigation of vitamin C as a potential adjuvant to mitigate hyperglycemia-associated skeletal muscle complications.