成年小鼠脊髓损伤后跑步机训练通过上调过氧化物酶体增殖物激活受体γ共激活剂1α促进髓鞘修复

Myelin repair of spinal cord injury in adult mice induced by treadmill training upregulated peroxisome proliferator-activated receptor gamma coactivator 1 alpha

越来越多的证据证明体育锻炼对脊髓损伤(SCI)后髓鞘再生和运动功能表现的有效性。然而,跑步机训练对SCI后髓鞘修复和功能恢复的分子机制尚未得到充分研究。本研究探讨了跑步机训练对小鼠胸T10挫伤模型中上调过氧化物酶体增殖物激活受体γ共激活剂1 α(PGC1α)介导的髓鞘修复和功能恢复的影响。对SCI的小鼠进行为期4周的跑步机训练计划。采用免疫荧光、RNA荧光原位杂交和Western blotting检测少突胶质细胞生成相关蛋白和PGC1α的表达水平。使用透射电子显微镜(TEM)观察髓鞘结构。Basso Mouse Scale(BMS)和CatWalk自动步态分析系统用于运动功能恢复评估,并检查了运动诱发电位(MEP)。此外,腺相关病毒(AAV)介导的少突胶质细胞(OLs)中PGC1α敲低被用来进一步揭示PGC1α在运动诱导的髓鞘再生中的作用。我们发现SCI之后跑步机训练可促进少突胶质细胞前体细胞(OPC)增殖,促进少突胶质细胞(OL)成熟,并增加髓鞘相关蛋白和髓鞘厚度,从而促进髓鞘修复和后肢功能表现以及神经传导的速度和幅度的改善。此外,通过AAV下调PGC1α减弱了跑步机训练的这些积极作用。总之,我们的结果表明跑步机训练通过上调PGC1α来增强髓鞘再生和功能恢复,这为理解体育锻炼对髓鞘修复的作用向前迈出了一步。

Growing evidence has proven the efficacy of physical exercise in remyelination and motor function perfor-mance after spinal cord injury(SCI).However,the molecular mechanisms of treadmill training on myelin repair and functional recovery after SCI have not yet been fully studied.Here,we explored the effect of treadmill training on up-regulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha(PGC1α)-mediated myelin repair and functional recovery in a mouse model of thoracic T10 contusion injury.A 4-week treadmill training scheme was con-ducted on mice with SCI.The expression levels of oligodendrogenesis-related protein and PGC1αwere detected by im-munofluorescence,RNA fluorescence in situ hybridization and western blotting.Transmission electron microscopy(TEM)was used to observe myelin structure.The Basso Mouse Scale(BMS)and CatWalk automated gait analysis sys-tem were used for motor function recovery evaluation.Motor evoked potentials(MEPs)were also identified.In addi-tion,adeno-associated virus(AAV)-mediated PGC1αknockdown in OLs was used to further unravel the role of PGC1αin exercise-induced remyelination.We found that treadmill training boosts oligodendrocyte precursor cells(OPCs)proliferation,potentiates oligodendrocytes(OLs)maturation,and increases myelin-related protein and myelin sheath thickness,thus impelling myelin repair and hindlimb functional performance as well as the speed and amplitude of nerve conduction after SCI.Additionally,downregulating PGC1αthrough AAV attenuated these positive effects of treadmill training.Collectively,our results suggest that treadmill training enhances remyelination and functional recov-ery by upregulating PGC1α,which should provide a step forward in the understanding of the effects of physical exer-cise on myelin repair.