Interval rehabilitation with intermittent rest modulates systemic immune response and improves healing following bone...

Rehabilitative exercise has shown potential to enhance bone healing, but the optimal design of exercise protocols following injury remains unclear. This study investigated how two rehabilitation parameters-progressive loading and intermittent rest between running bouts-influence bone regeneration and the systemic immune response following traumatic femoral defects in rodents. Rehabilitation protocols with varying treadmill inclines were applied after 3 mm segmental bone defects. Despite incorporating gradual or delayed increases in treadmill incline, all groups exhibited minimal bone formation and high nonunion rates, suggesting that these treadmill protocols may be insufficient to promote healing in 3 mm defects. Next, we tested whether incorporating one minute of intermittent rest in between every minute of treadmill running could enhance regeneration in bilateral femoral defects (2 mm and 3 mm). Interval running with intermittent rest significantly increased bone volume in 3 mm defects and resulted in a near-significant improvement in 2 mm defects compared to continuous running and sedentary controls. Flow cytometry of longitudinal blood samples revealed that interval running also resulted in a more accelerated reduction of circulating MDSCs toward baseline levels than continuous treadmill running without intermittent rest and sedentary controls. Treadmill interval running also significantly reduced monocyte levels one week after post-injury rehabilitation began. These findings suggest that interval running with intermittent rest can attenuate injury-induced inflammation while improving bone outcomes, highlighting the therapeutic potential of interval exercise regimens to promote mechanical and immunological environments favorable for bone repair. This work advances our understanding of how exercise design can be optimized to improve post-injury healing outcomes.