Exerkine-loaded exosomes in muscle aging: a nexus of exercise, regeneration, and crosstalk

This review examines the critical role of extracellular vesicles, specifically exosomes, as mediators of intercellular and inter-organ communication in the context of skeletal muscle aging and regeneration. Skeletal muscle, traditionally viewed as a simple contractile tissue, is now recognized as a potent endocrine organ that secretes a diverse array of signaling molecules, collectively termed "exerkines," in response to physical activity. We integrate contemporary evidence demonstrating how exercise modulates the release and molecular composition of muscle-derived exosomes, which in turn influence key cellular processes. The report details how exosomal cargo, including non-coding RNAs and proteins, regulates muscle stem cell activation and differentiation, counteracts age-related decline (sarcopenia) by modulating protein homeostasis and inflammation, and facilitates systemic metabolic crosstalk with distant tissues such as adipose tissue. We also critically discuss the burgeoning therapeutic potential of engineered exosomes for musculoskeletal health, while highlighting significant and interconnected challenges in the field, including the lack of standardized methodologies and regulatory frameworks. This review provides a nuanced perspective on the "exerkine" hypothesis, underscoring the potential of exercise-modulated exosomes as both diagnostic biomarkers and novel therapeutic agents for maintaining lifelong muscle health.