Role of LPC 18:1 in the Lipid Metabolic Response to Combined Vitamin D and Resistance Exercise for Protecting Diabetic Skeletal Muscle Function

PURPOSE: We have previously found that vitamin D and resistance exercise synergistically improve type 2 diabetes mellitus (T2DM)-related skeletal muscle atrophy. This study aims to investigate the effect of varying exercise intensity on synergistic effects of vitamin D and resistance exercise on their efficacy in improving T2DM-induced myopathy and to further elucidate the underlying mechanism. METHODS: We compared the effects of vitamin D combined with low-, moderate-, and high-intensity resistance exercise on metabolic status and skeletal muscle function. Then, we explored the mechanism through lipidomic analysis in diabetic rats and verified in adults with T2DM. RESULTS: We found that combined intervention of vitamin D and medium-resistivity volume (MRV) exercise most effectively improved glucose metabolism and insulin sensitivity and increased muscular mass and strength, resulting to alleviated gastrocnemius muscle atrophy in diabetic rats. Vitamin D combined with MRV intervention increased expressions of vitamin D receptor, whereas lysophosphatidylcholine acyltransferase 3, activated p38 MAPK, and ERK1/2 signaling pathways suppressed inflammatory responses. Moreover, lipidomic analysis of gastrocnemius muscle indicated that lysophosphatidylcholine (LPC) 18:1 exhibited the most significant restoration after intervention. Notably, in adults with T2DM, reduced changes in plasma LPC 18:1 levels exhibited positive correlations with decreased appendicular skeletal muscle index, upper limb muscle mass, and thigh muscle mass. CONCLUSIONS: Our findings suggested that vitamin D combined with MRV intervention has more pronounced effect on improving T2DM-related skeletal muscle atrophy. Additionally, LPC 18:1 may be a key target for regulating skeletal muscle function through p38 MAPK/ERK and inflammatory signaling pathways. These results provide novel insights for the prevention and treatment of T2DM-related skeletal muscle atrophy through lifestyle modifications.