Chinese leek-derived extracellular vesicles ameliorate sarcopenia by regulating mitochondrial biogenesis and autophagy via AMPK and maintaining myosin homeostasis.

Abstract

Sarcopenia, a prevalent age-related degenerative disorder, poses significant challenges in geriatric care. Chinese leek demonstrates therapeutic potential against sarcopenia progression, with emerging evidence suggesting its extracellular vesicles (EVs) may mediate these effects. Notably, plant-derived EVs have garnered increasing attention due to their low immunogenicity and capacity for cross-kingdom molecular delivery. This study investigates Chinese leek-derived EVs (CL-EVs) as novel regulators of muscle homeostasis through multi-omics approaches. CL-EVs were isolated via differential ultracentrifugation and characterized using nanoparticle tracking analysis, TEM, and proteomic profiling. Using a dexamethasone (DEX)-induced C2C12 myotube atrophy model, we demonstrated CL-EVs' cellular internalization and dose-dependent restoration of myotube diameter. CL-EVs significantly alleviated DEX-induced mitochondrial impairment in C2C12 cells, evidenced by restored ATP production, reduced ROS levels, and stabilized mitochondrial membrane potential (MMP). Multi-omics analysis revealed CL-EVs activate the AMPK/SIRT1/PGC-1α axis, confirmed by Western blotting. Proteomic analysis identified selenium-associated proteins in CL-EVs. Expanding on selenocompounds' known anti-proteolytic effects through Akt modulation, we demonstrate CL-EVs attenuate myotube atrophy through dual mechanisms: inactivation of Akt/FoxO3a/Atrogin-1/MuRF1 proteolytic signaling and activation of mitochondrial biogenesis/mitophagy pathways, collectively improving muscle homeostasis. To investigate gut-muscle axis interactions, 16 S rDNA sequencing and untargeted metabolomic profiling were performed on fecal samples. CL-EVs treatment attenuated DEX-induced gut microbiota dysbiosis and correlated metabolic abnormalities in sarcopenic mice. This study establishes CL-EVs as novel regulators of muscle homeostasis through dual modulation of AMPK/SIRT1/PGC-1α activation and Akt/FoxO3a/Atrogin-1/MuRF1 inhibition. This innovative "multi-target & gut-muscle axis" paradigm provides a groundbreaking strategy for sarcopenia therapeutics.