Spatiotemporal dynamics of exercise-induced macrophages influences axonal regeneration after peripheral nerve injury

This study aimed to elucidate the relationship between the spatiotemporal behavior of macrophages during exercise and axonal regeneration following peripheral nerve injury. A sciatic nerve crush model was created using male C57BL/6J mice, which were divided into sedentary and exercise groups. The exercise group performed low-intensity treadmill running (10 m/min, 60 min/day, 5 days/week) starting 3 days post-injury. Immunohistochemical analyses of Neurofilament 200 kDa (NF200), Growth Associated Protein-43 (GAP-43), F4/80, and arginase-1 (Arg-1), a representative marker of M2 macrophages and a downstream effector of the JAK-STAT6 signaling pathway, were conducted in the proximal and distal regions of the injured nerves. Functional recovery was assessed using the sciatic functional index (SFI) and compound muscle action potential (CMAP). At 7 and 14 days post-injury, the exercised group exhibited a significant increase in axonal number and Arg-1-positive area, specifically in the distal region. SFI and CMAP analyses also demonstrated enhanced functional recovery in the exercise group. These findings suggest that low-intensity treadmill exercise may enhance axonal regeneration, potentially through transient activation and local accumulation of M2-polarized macrophages. Therefore, exercise-induced regulation of macrophage dynamics may represent a novel therapeutic strategy for peripheral nerve repair.