Targeted energy metabolomics analysis-based mitochondrial restoration: Nutritional intervention of dairy-derived MFG-E8 synergistic with egg yolk phosphatidylcholine in skeletal muscle regeneration.

This study explores the therapeutic potential and mechanistic basis of a novel dairy-egg derived nutritional intervention-combining milk fat globule-epidermal growth factor 8 (MFG-E8) and egg yolk phosphatidylcholine (PC)-against dexamethasone (Dex)-induced skeletal muscle atrophy in aged rats. Specifically, we aimed to determine whether MFG-E8 + PC co-supplementation could mitigate muscle atrophy, improve mitochondrial function and elucidate the underlying mechanisms involving energy metabolism. By integrating targeted energy metabolomics, we demonstrate that the synergistic action of MFG-E8 and PC alleviates muscle atrophy in aged rats by restoring mitochondrial function and energy metabolism. Dietary supplementation with MFG-E8 + PC significantly reversed Dex-induced reductions in body mass and swimming endurance, while ameliorating histopathological features of muscle atrophy. Mechanistically, MFG-E8 + PC upregulated tricarboxylic acid (TCA) cycle intermediates (e.g., citrate, α-ketoglutarate, malate) and enhanced glycolysis and oxidative phosphorylation (OXPHOS) by reactivating rate-limiting enzymes (hexokinase, phosphofructokinase-1, citrate synthase). This metabolic regulation was linked to increased mitochondrial biogenesis via the AMPK/PGC-1α/Nrf1 axis and elevated expression of respiratory chain complexes. Notably, the dairy-egg synergy mitigated oxidative stress by restoring mitochondrial membrane potential and reducing reactive oxygen species, highlighting its dual role in energy metabolism and antioxidant protection. These findings position MFG-E8 and PC as promising functional food components for muscle health, offering a dietary strategy to combat age- or stress-related muscle wasting through mitochondrial-targeted nutritional intervention.