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

ABSTRACT 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 impact of varying exercise intensity on synergistic effects of vitamin D and resistance exercise on their efficacy in improving type 2 diabetes mellitus (T2DM)-induced myopathy, and 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, 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 and lysophosphatidylcholine acyltransferase 3, activated p38 MAPK and ERK1/2 signaling pathways, whereas 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.