Exercise Ameliorates Dysregulated Mitochondrial Fission, Mitochondrial Respiration, and Neuronal Apoptosis in Parkinson's Disease Mice via the Irisin/AMPK/SIRT1 Pathway.

Mitochondrial dysfunction plays a crucial role in the pathogenesis of Parkinson's disease (PD), yet therapeutic strategies targeting mitochondrial function remain limited. Exercise has shown neuroprotective benefits in PD, but the underlying mechanisms are not fully understood. This study aimed to investigate how exercise affects MPTP-induced excessive apoptosis, mitochondrial fission, and mitochondrial function in PD mice, with a focus on the Irisin/AMPK/SIRT1 pathway. Thirty-two male C57BL/6 J mice, aged 7-8 weeks, were randomly assigned to control (n = 8) and experimental groups (n = 24). Mice in the experimental groups were administered intraperitoneal injections of MPTP to induce the PD model. Subsequently, the experimental mice were divided into three groups (8 mice in each group): the sedentary group (PD), the group subjected to 10 weeks of treadmill exercise (PDEX), and the group receiving both treadmill exercise and Irisin antagonist injections (EXRG). Upon completion of the 10-week intervention, behavioral assessments were performed. Following this, the mice were euthanized to collect brain samples and subjected to immunohistochemistry, immunofluorescence, ELISA, citrate synthase assay, and Western blot analyses. MPTP-treated mice exhibited significant motor dysfunction and dopaminergic neuron loss in the nigrostriatal regions, which were alleviated after a 10-week exercise intervention. Exercise significantly reduced MPTP-induced neuronal apoptosis, as evidenced by decreased cellular debris and abnormal nuclear morphology, increased Bcl-2 protein levels, and decreased BAX expression. Furthermore, exercise mitigated abnormal mitochondrial fission in PD mice and improved mitochondrial function-related markers. This was reflected by reduced immunohistochemical signals and protein expression levels of Drp1, Fis1, and MFF, as well as increased citrate synthase activity and elevated expression levels of COX-I and COX-IV. In the substantia nigra of PD mice, the expression levels of Irisin, p-AMPK, and SIRT1 were reduced but were notably elevated after the 10-week exercise intervention. However, chronic treatment with Cyclo RGDyk to block Irisin signaling potentially counteracted the exercise-induced increases in p-AMPK and Sirt1 expression. Moreover, blocking the Irisin signaling pathway reversed the beneficial effects of exercise on mitochondrial fission, mitochondrial function, and neuronal apoptosis. Exercise is an effective approach for alleviating PD pathology by reducing excessive mitochondrial fission, dysregulated mitochondrial respiration and metabolism, and neuronal loss. The neuroprotective effects of exercise are achieved, in part, by regulating the Irisin/AMPK/SIRT1 signaling pathway. This study underscores the potential of targeting Irisin signaling as a therapeutic strategy of exercise to enhance mitochondrial function and promote neuronal survival in PD.