Shockwave-Induced Myoblast Exosome-Like Vesicles: Emerging Drivers of Muscle Regeneration.

Exosomes, a subset of nanosized extracellular vesicles, are key mediators of intracellular communication that show growing therapeutic potential in skeletal muscle regeneration. By shuttling bioactive cargoes between cells, they modulate recipient cell behavior, influencing proliferation, differentiation, and tissue remodeling. Previous studies demonstrated that different tensile load regimes can modulate both the production and regenerative capacity of myoblast-derived exosomes, positioning mechanically induced vesicle release as a potential driver of morpho-functional adaptations required for myoblast differentiation and myotube formation. Within this framework, shockwave (SW) therapy is gaining increasing attention as a non-invasive mechanical stimulus in regenerative medicine; however, the precise cellular mechanisms linking SW stimulation and tissue repair remain poorly understood. Preclinical evidence shows that extracellular vesicles (EVs) derived from SW-treated cardiomyocytes possess pro-angiogenic and regenerative properties, suggesting that SW-induced paracrine signaling may be conserved across tissues. In this study, we investigated whether in vitro SW treatment affects myogenic exosome release, contributing to SW-mediated muscle regeneration. Tunable Resistive Pore Sensing analysis revealed a significant increase in EV concentration at 6 h post-treatment, with no detectable differences between treated cells and controls at 12 h, indicating a rapid and transient secretory response. Importantly, vesicle size distribution remained unchanged across conditions, suggesting that SW primarily modulates EV production dynamics rather than vesicle morphology. Ultrastructural analyses further confirmed this transient activation, showing vesicular trafficking and exosome-like EV secretion in treated myoblasts. Further mechanistic insights into SW-induced exosome release may uncover novel pathways, contributing to SW regenerative effects supporting its translational application to muscle injuries and disorders.