Voluntary exercise alleviates ischemic brain injury in mice by modulating mitochondrial dysfunction

Document Type : Original Article

Authors

1 Tongde Hospital of Zhejiang Province, No. 234, Gucui Road, Hangzhou, Zhejiang, China

2 The First Affiliated Hospital of Zhejiang University of Chinese Medicine, No. 54, Post and Telecommunication Road, Hangzhou, Zhejiang, China

10.22038/ijbms.2025.80783.17488

Abstract

Objective(s): The relationship between exercise and mitochondrial function is unclear. This study investigated the relationship between voluntary exercise and mitochondrial dynamics in ischemic stroke model mice.
Materials and Methods: This experiment used 54 male C57BL/6 J mice to assess the therapeutic effect of voluntary exercise on ischemic stroke in a middle cerebral artery occlusion (MCAO) model. Body weight and the number of wheel turns were recorded to monitor the physiological condition of the mice. The degree of brain injury was evaluated via hematoxylin and eosin (H&E) staining and measurement of the cerebral infarction volume. Western blotting and immunofluorescence were used to measure dynein-1-like protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and optic atrophy type 1 (OPA1) levels to assess mitochondrial dynamics and analyze the degree of mitochondrial apoptosis by measuring cytochrome c (CYT-C), cleaved caspase-3, and caspase-3 expression. 
Results: Voluntary exercise positively affected the behavioral score and infarct volume. H&E staining revealed that voluntary exercise reversed MCAO-induced cortical damage. Furthermore, voluntary exercise improved mitochondrial dynamics by inhibiting DRP1 and FIS1 expression and inducing OPA1 expression. Additionally, the mitochondrial apoptosis pathway was inhibited by down-regulating the expression of CYT-C, cleaved caspase-3, and caspase-3.
Conclusion: Voluntary exercise exerts a significant neuroprotective effect against MCAO-induced brain injury by regulating mitochondrial dynamics and the mitochondrial apoptotic pathway.

Keywords

Main Subjects

References

1. Shichita T, Ooboshi H, Yoshimura A. Neuroimmune mechanisms and therapies mediating post-ischaemic brain injury and repair. Nat Rev Neurosci 2023; 24: 299-312.
2. Tsivgoulis G, Katsanos A, Sandset E, Turc G, Nguyen T, Bivard A, et al. Thrombolysis for acute ischaemic stroke: Current status and future perspectives. Lancet Neurol 2023; 22: 418-429.
3. Shiv KS, Damanpreet S. Mitochondrial mechanisms in cerebral ischemia-reperfusion injury: Unravelling the intricacies. Mitochondrion 2024; 77: 101883.
4. Borchers A, Pieler T. Programming pluripotent precursor cells derived from Xenopus embryos to generate specific tissues and organs. Genes (Basel) 2010; 1: 413-426.
5. Song H, Zhang X, Wang J, Wu Y, Xiong T, Shen J, et al. The regulatory role of adipocyte mitochondrial homeostasis in metabolism-related diseases. Front Physiol 2023;14: 1261204-1261218.
6. Chen H, Wu C, Lv Q, Li M, Ren L. Targeting mitochondrial homeostasis: the role of acupuncture in depression treatment. Neuropsychiatr Dis Treat 2023; 19: 1741-1753.
7. Zhao J, Guo J, Chen Y, Li W, Zhou P, Zhu G, et al. Improving rehabilitation motivation and motor learning ability of stroke patients using different reward strategies: Study protocol for a single-center, randomized controlled trial. Front Neurol 2024; 15: 1418247-1418255.
8. Landsmann B, Pinter D, Pirker E, Pichler G, Schippinger W, Weiss EM, et al. An exploratory intervention study suggests clinical benefits of training in chronic stroke to be paralleled by changes in brain activity using repeated fMRI. Clin Interv Aging 2016; 11: 97-103.
9. Khan M. Rehabilitation in animal models of stroke. Phys Ther Res 2023; 26: 39-43.
10. Huixia G, Min L, Jing T, Qing L, Ruiling L, Lai W. Early rehabilitation exercise after stroke improves neurological recovery through enhancing angiogenesis in patients and cerebral ischemia rat model. Int J Mol Sci 2022; 23: 10508-10524.
11. Pan G, Zhang H, Zhu A, Lin Y, Zhang L, Ye B, et al. Treadmill exercise attenuates cerebral ischaemic injury in rats by protecting mitochondrial function via enhancement of caveolin-1. Life Sci 2021; 264: 118634.
12. Zhu A, Lin Y, Hu X, Lin Z, Lin Y, Xie Q, et al. Treadmill exercise decreases cerebral edema in rats with local cerebral infarction by modulating AQP4 polar expression through the caveolin-1/TRPV4 signaling pathway. Brain Res Bullet 2022; 188: 155-168.
13. Zhai Y, Luo Y, Mo X, Yang P, Pang Y, Wu L, et al. Zhuang medicine shuanglu tongnao compound recipe treats stroke by affecting the intestinal flora regulated by the TLR4/NF-κB signaling pathway. Ann Transl Med 2023;11:174-191.
14. Xu Y, Zhang J, Gao F, Cheng W, Zhang Y, Wei C, et al. Engeletin alleviates cerebral ischemia reperfusion-induced neuroinflammation via the HMGB1/TLR4/NF-kappaB network. J Cell Mol Med 2023; 27:1653-1663.
15. Zhan F, Dong Y, Zhou L, Li X, Zhou Z, Xu G. Minocycline alleviates LPS-induced cognitive dysfunction in mice by inhibiting the NLRP3/caspase-1 pathway. Aging 2024; 16: 2989-3006.
16. Xu F, Tian Z, Wang Z. Cilostazol protects against degenerative cervical myelopathy injury and cell pyroptosis via TXNIP-NLRP3 pathway. Cell Div 2024; 19: 2-15.
17. Trevino TN, Almousawi AA, Robinson KF, Fogel AB, Class J, Minshall RD, et al. Caveolin-1 mediates blood-brain barrier permeability, neuroinflammation, and cognitive impairment in SARS-CoV-2 infection. J Neuroimmunol 2024; 388: 578309-578325.
18. Tu W-J, Wang L-D, Yan F, Peng B, Hua Y, Liu M, et al. China stroke surveillance report 2021. Mil Med Res 2023; 10: 33-49.
19. Zhang D, Lu Y, Zhao X, Zhang Q, Li L. Aerobic exercise attenuates neurodegeneration and promotes functional recovery – Why it matters for neurorehabilitation & neural repair. Neurochem Int 2020; 141: 104862.
20. Zurine DM, Nathalie K, Michael J B, Benoit L, Drew W, Niclas O, et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 2021; 600: 494-499.
21. Hood DA, Memme JM, Oliveira AN, Triolo M. Maintenance of skeletal muscle mitochondria in health, exercise, and aging. Ann Rev Physiol 2019; 81: 19-41.
22. Wang J, Jiang W, Xin J, Xue W, Shi C, Wen J, et al. Caveolin-1 alleviates acetaminophen-induced fat accumulation in non-alcoholic fatty liver disease by enhancing hepatic antioxidant ability via activating AMPK pathway. Front Pharmacol 2021; 12: 717276-717292.
23. Qian W, Jiao L, Zhiguo M, Liyu T, Ning W, Guangyun W, et al. Ligustilide attenuates ischemic stroke injury by promoting Drp1-mediated mitochondrial fission via activation of AMPK. Phytomedicine 2021; 95: 153884.
24. Shashank D, Cristiana Z, Ana J G-S. Mechanisms of mitochondrial cell death. Biochem Soc Trans 2021; 49: 663-674.
25. Philipp W, Axel S, Frank E. Proapoptotic complexes of BAX and BAK on the outer mitochondrial membrane. Biochim Biophys Acta Mol Cell Res 2022; 1869: 119317-119328.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 7
July 2025
Pages 846-851

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