Effects of different intensities treadmill exercise on cortical mTOR pathway and skilled motor function recovery in spinal cord injury

Abstract Treadmill exercise is beneficial for spinal cord injury (SCI) both in bench and in bedside, but the most effective treadmill exercise intensity and mechanisms underlying the treadmill exercise on skilled motor function recovery remain elusive. Here, the improved skilled motor function recovery, enhanced nerve conduction capability, neuroplasticity, and axonal sprouting were observed in the SCI mice after training for 4 weeks. However, high exercise intensity (HEI) leads to vulnerability and impaired exercise tolerance during training. We further found that in the moderate exercise intensity (MEI) and HEI groups showed elevated expression of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1). Meanwhile, elevated phosphorylated levels of ribosomal protein S6 (p-S6) and protein kinase B (p-AKT) in mouse motor cortex were also observed, indicating the cortical mechanistic target of rapamycin (mTOR) pathway activation. To investigate the role of the cortical mTOR activation, we performed a rapamycin assay. After using rapamycin, the exercise-induced activation of the cortical mTOR pathway and the exercise-enhanced effects were inhibited. Together, the expression of neurotrophic factors and the activation of the cortical mTOR pathway are in an intensity-dependent manner. And the MEI is safer and more beneficial than the LEI and HEI. Based on the rapamycin assay, the exercise-induced activation of mTOR pathway is necessary for the enhanced motor cortex and spine remodeling, all of which further contribute to better-skilled motor function recovery. These dates may provide a new window to further understand the mechanisms underlying exercise training effects on the skilled motor function recovery following SCI.