Exercise Mitigates MPTP-Induced Mitochondrial Fragmentation through the Irisin/AMPK/SIRT1 Pathway

Purpose 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 and mitochondrial fission in PD mice, with a focus on the irisin/AMPK/SIRT1 pathway. Methods Thirty-two male C57BL/6J 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 ten weeks of treadmill exercise (PDEX), and the group receiving both treadmill exercise and irisin antagonist injections (EXRG). Upon completion of the ten-week intervention, behavioral assessments were performed. Following this, the mice were euthanized to collect brain samples and subjected to immunohistochemistry, immunofluorescence, ELISA, and Western blot analyses. Results MPTP-treated mice exhibited significant motor dysfunction and dopaminergic neuron loss in the nigrostriatal regions, which were ameliorated by a 10-week exercise intervention. Exercise notably reduced MPTP-induced neuronal apoptosis, as evidenced by decreased cellular fragments and abnormal nuclear morphology, increased Bcl-2 protein levels, and decreased Bax expression. Additionally, exercise mitigated abnormal mitochondrial fission in PD mice, as shown by reduced immunohistochemistry and protein expression of Drp1, Fis1, and MFF. In the substantia nigra of PD mice, the expression levels of irisin, p-AMPK, and SIRT1 were decreased but were elevated following the 10-week exercise intervention. However, blocking the irisin signaling by chronic treatment with cyclo RGDyk potentially counteracted the exercise-induced elevations in p-AMPK and Sirt1 expression. Moreover, the beneficial effects of exercise on neuronal apoptosis and mitochondrial fission were reversed by blocking irisin signaling pathways. Conclusion These findings suggest that regular exercise is beneficial in alleviating motor dysfunction in MPTP-treated mice, partly achieved through the preservation of dopaminergic neurons, reduction of excessive neuronal apoptosis, and improvement of normal mitochondrial fission. The excise-associated neuroprotective effects are likely linked to the irisin/AMPK/Sirt1 signalling pathway.