Extracorporeal Shock Wave Therapy Promotes Peripheral Nerve Regeneration Through ERK1/2-Mediated Autophagy

Extracorporeal shock wave therapy (SWT) has shown potential in promoting peripheral nerve regeneration, yet its underlying mechanisms remain incompletely understood. In this study, we explored the role of extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated autophagy in SWT-enhanced nerve repair using both in vivo and in vitro models. Application of SWT to transected sciatic nerves in rats led to increased ERK1/2 phosphorylation and upregulation of the autophagy marker LC3B, as confirmed by immunofluorescence and RT-qPCR. In vitro, SWT-treated Schwann cells exhibited enhanced autophagosome formation and accelerated autophagic flux, correlating with increased axonal outgrowth in cocultured dorsal root ganglion neurons. Pharmacological modulation further revealed that ERK1/2 activation enhanced, while inhibition suppressed, SWT-induced autophagy and neurite extension. Moreover, SWT improved motor recovery in injured rats, as evidenced by enhanced gait performance, sciatic functional index, and electrophysiological recordings. These effects were amplified by cotreatment with the ERK1/2 agonist senkyunolide I and attenuated by the inhibitor SCH772984. Histological and ultrastructural analyses showed enhanced Schwann cell proliferation, axonal integrity, and myelin reorganization following SWT, alongside improved muscle morphology. Collectively, our findings identify ERK1/2-activated autophagy in Schwann cells as a key mechanism mediating the therapeutic effects of SWT, supporting its translational potential for peripheral nerve repair.