Zhao Qin, Li Ci, Xu Yangjie, Zhong Juan, Liu Hongzhen, Yin Ying, Liu Yuan, Yang Ce, Yu Lehua, Liu Li, Pan Lu, Tan Botao
Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Chongqing 400010, China; Department of Rehabilitation Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jingwu Weiqi Road, Huaiyin District, Jinan, Shandong province 250000, China.
Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jingwu Weiqi Road, Huaiyin District, Jinan, Shandong province 250000, China.
Exp Neurol. 2025 Mar;385:115096. doi: 10.1016/j.expneurol.2024.115096. Epub 2024 Dec 8.
Regeneration of the corticospinal tract (CST) is considered a therapeutic target to achieve improved recovery of motor function after spinal cord injury (SCI), which is an incurable CNS damage that affects millions of people. Exercise training is effective in improving multiple functions in spinal cord-injured patients. However, the effects of exercise training on axon regeneration have not been sufficiently reported. Osteopontin (OPN) has great potential application as a neuroprotective agent for the repair of the nervous system. Studies have shown that the extent of axon regeneration strongly correlates with the expression of OPN. Our previous studies demonstrated that treadmill exercise supplemented by OPN enhances motor function recovery, but axon regeneration is still limited. Extending the treadmill exercise for 12 weeks, we observed promoted axon regeneration, motor function improvement, and signaling pathway activation in mice with SCI after supplementing OPN. Axon regeneration was observed with an anterograde tracer, motor function recovery was evaluated by animal ethology and electrophysiology, and the levels of IGF-1R/Akt/mTOR signaling pathway were evaluated. The results showed that the CST of C5 crushed mice regenerated and formed synaptic connections with neurons after treadmill exercise supplemented by OPN, the horizontal ladder and cylinder rearing test of injured limbs were improved, motor evoked potential also suggested enhanced nerve conduction, and the expression of p-IR, p-Akt, and p-S6 were increased. And the improvements were more obvious than that of the exercise group. Collectively, our study found that treadmill exercise supplemented by OPN promote axon regeneration and motor function through the IGF-1R/Akt/mTOR signaling pathways, and these improvements can be inhibited by rapamycin and Methyl-β-CD(M-B-CD).
皮质脊髓束（CST）的再生被视为脊髓损伤（SCI）后实现运动功能更好恢复的治疗靶点，脊髓损伤是一种影响数百万人的无法治愈的中枢神经系统损伤。运动训练对改善脊髓损伤患者的多种功能有效。然而，运动训练对轴突再生的影响尚未得到充分报道。骨桥蛋白（OPN）作为一种用于修复神经系统的神经保护剂具有巨大的潜在应用价值。研究表明，轴突再生的程度与OPN的表达密切相关。我们之前的研究表明，补充OPN的跑步机运动可增强运动功能恢复，但轴突再生仍然有限。在补充OPN后，将跑步机运动延长至12周，我们观察到脊髓损伤小鼠的轴突再生得到促进、运动功能改善以及信号通路激活。使用顺行示踪剂观察轴突再生，通过动物行为学和电生理学评估运动功能恢复，并评估IGF-1R/Akt/mTOR信号通路的水平。结果显示，补充OPN的跑步机运动后，C5损伤小鼠的CST再生并与神经元形成突触连接，受伤肢体的水平阶梯和圆筒饲养试验得到改善，运动诱发电位也表明神经传导增强，并且p-IR、p-Akt和p-S6的表达增加。而且这些改善比运动组更明显。总体而言，我们的研究发现，补充OPN的跑步机运动通过IGF-1R/Akt/mTOR信号通路促进轴突再生和运动功能，而雷帕霉素和甲基-β-环糊精（M-B-CD）可抑制这些改善。
