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运动预处理通过改善线粒体功能缓解MPTP诱导的帕金森小鼠运动障碍

徐苗苗^1,2, 胡丹婷¹, 张侨², 刘晓光³, 李兆伟¹, 陆丽明^2,*

¹广州中医药大学体育健康学院，广州 510006；²广州中医药大学针灸康复临床医学院，广州 510006；³广州体育学院运动与健康学院，广州 510620

摘要

帕金森病(Parkinson's disease, PD)是常见的神经系统疾病，主要与中脑黑质多巴胺能神经元线粒体功能障碍相关。近年来，运动干预在PD早期预防中的作用备受关注，但研究仍较为有限。本研究旨在探讨运动预处理对1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP)诱导的PD小鼠模型运动障碍及中脑黑质线粒体功能的影响。选取8周龄C57BL/6J雄性小鼠，随机分为静坐+盐水(sedentary + saline, SS)组、静坐+MPTP (sedentary + MPTP, SM)组、运动+盐水(exercise + saline, ES)组和运动+MPTP (exercise + MPTP, EM)组，每组18只。ES和EM组进行4周跑台训练，随后SM和EM组接受连续5天腹腔注射MPTP以构建PD模型。通过旷场、爬杆、转棒和抓力实验评估运动功能，并采用免疫组织化学染色、Western blot及透射电镜技术检测中脑黑质多巴胺能神经元和线粒体的形态与功能变化。结果显示，与SM组相比，EM组小鼠运动能力显著改善，中脑酪氨酸羟化酶(tyrosine hydroxylase, TH)和多巴胺转运体(dopamine transporter, DAT)蛋白表达水平显著上调，中脑黑质线粒体α-突触核蛋白(α-synuclein, α-Syn)表达显著下调；与SM组相比，EM组中脑黑质线粒体融合蛋白视神经萎缩蛋白1 (optic atrophy protein 1, OPA1)、线粒体融合蛋白2 (mitofusin 2, MFN2)及生物发生相关蛋白过氧化物酶体增殖物激活受体γ共激活因子1α (peroxisome proliferator-activated receptor gamma coactivator 1α, PGC-1α)、线粒体转录因子A (mitochondrial transcription factor A, TFAM)蛋白表达水平上调，分裂蛋白动力相关蛋白1 (dynamin-relatedprotein 1, DRP1)和线粒体分裂因子1 (mitochondrial fission 1 protein, FIS1)蛋白表达水平显著下调。与SM组相比，EM组中脑黑质线粒体损伤明显减轻，线粒体膜电位和ATP生成水平恢复，活性氧(reactive oxygen species, ROS)水平下降。以上结果提示，4周的预跑台训练通过改善线粒体功能缓解MPTP诱导的PD小鼠运动障碍，本研究为PD的早期预防提供新视角，证明运动干预在PD防治中的潜在价值，并为制定有效的运动干预策略提供理论依据。

关键词： 帕金森病; 预跑台训练; 线粒体功能; 多巴胺能神经元; 线粒体动力学

Exercise preconditioning alleviates motor deficits in MPTP-induced Parkinsonian mice by improving mitochondrial function

XU Miao-Miao^1,2, HU Dan-Ting¹, ZHANG Qiao², LIU Xiao-Guang³, LI Zhao-Wei¹, LU Li-Ming^2,*

¹School of Sports and Health, Guangzhou University of Chinese Medicine, Guangzhou 510006, China；²Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou 510006, China；³School of Exercise and Health, Guangzhou Sport University, Guangzhou 510620, China

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder mainly related to mitochondrial dysfunction of dopami nergic neurons in the midbrain substantia nigra. This study aimed to investigate the effects of exercise preconditioning on motor deficits and mitochondrial function in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Eight-weekold male C57BL/6J mice were randomly divided into four groups: sedentary + saline (SS), sedentary + MPTP (SM), exercise + saline (ES), and exercise + MPTP (EM) groups. Mice in the ES and EM groups received 4 weeks of treadmill training, and then SM and EM groups were treated with MPTP for 5 days. Motor function was assessed by behavioral tests, and morphological and functional changes in dopaminergic neurons and mitochondria in the substantia nigra of the midbrain were evaluated using immunohistochemistry, Western blot, and transmission electron microscopy technology. The results showed that, compared with the SM group, the EM group exhibited significantly improved motor ability, up-regulated protein expression levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the midbrain, and down-regulated protein expression of α-synuclein (α-Syn) in the mitochondria of substantia nigra. Compared with the SM group, the EM group showed up-regulated protein expression levels of mitochondrial fusion proteins, including optical atrophy protein 1 (OPA1) and mitofusin 2 (MFN2), and biogenesis-related proteins, including peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM), while the protein expression levels of dynamin-related protein 1 (DRP1) and mitochondrial fission protein 1 (FIS1) were significantly down-regulated. Compared with the SM group, the EM group showed significantly reduced damage to substantia nigra mitochondria, restored mitochondrial membrane potential and ATP production, and decreased levels of reactive oxygen species (ROS). These results suggest that 4-week treadmill pre-training can alleviate MPTP-induced motor impairments in PD mice by improving mitochondrial function, providing a theoretical basis for early exercise-based prevention of PD.

Key words: Parkinson''s disease; treadmill pre-training; mitochondrial function; dopaminergic neurons; mitochondrial dynamics

收稿日期：　　录用日期：

通讯作者：陆丽明　　E-mail:

DOI: 10.13294/j.aps.2025.0049

引用本文：

徐苗苗, 胡丹婷, 张侨, 刘晓光, 李兆伟, 陆丽明. 运动预处理通过改善线粒体功能缓解MPTP诱导的帕金森小鼠运动障碍[J]. 生理学报 2025; 77 (3): 419-431.

XU Miao-Miao, HU Dan-Ting, ZHANG Qiao, LIU Xiao-Guang, LI Zhao-Wei, LU Li-Ming. Exercise preconditioning alleviates motor deficits in MPTP-induced Parkinsonian mice by improving mitochondrial function. Acta Physiol Sin 2025; 77 (3): 419-431 (in Chinese with English abstract).