1- Department of Physical Education, Sa.C., Islamic Azad University, Sanandaj, Iran
2- Department of Physical Education, Sa.C., Islamic Azad University, Sanandaj, Iran ,kazizbeigi@iau.ac.ir
2- Department of Physical Education, Sa.C., Islamic Azad University, Sanandaj, Iran ,
Abstract: (91 Views)
Background: Mitochondrial proteostasis disruption in Alzheimer’s disease (AD) results in impaired mitochondrial autophagy (mitophagy). This study evaluated the effects of 8-week aerobic exercise training (T), resveratrol (RSV) supplementation, and their combination on mitophagy markers in an AD rat model.
Methods: In this experimental study, 35 male Wistar rats were divided into five groups: Control (NO), Alzheimer’s (AD), Alzheimer’s-Training (ADT), Alzheimer’s-Resveratrol (ADRSV), and Alzheimer’s-Training-Resveratrol (ADTRSV). RSV groups received 20 mg/kg/day orally. The aerobic exercise protocol consisted of treadmill running (6–18 m/min) five days per week for eight weeks. Hippocampal PINK1 and PARKIN expression levels were analyzed.
Results: AD induction significantly reduced PINK1 and PARKIN expression (P < 0.001). Compared to the AD group, significant increases in PINK1 and PARKIN were observed in the ADT (P = 0.043; P = 0.005), ADRSV (P = 0.033; P = 0.046), and ADTRSV (P < 0.001) groups. The ADTRSV group showed higher PINK1 expression than ADT (P = 0.036) and ADRSV (P = 0.046), and greater PARKIN expression than ADRSV (P = 0.046).
Conclusion: Exercise training and RSV supplementation improved hippocampal mitophagy in AD rats, with synergistic effects observed in the combined intervention. These findings suggest that non-pharmacological strategies may mitigate AD-related mitochondrial dysfunction.
Methods: In this experimental study, 35 male Wistar rats were divided into five groups: Control (NO), Alzheimer’s (AD), Alzheimer’s-Training (ADT), Alzheimer’s-Resveratrol (ADRSV), and Alzheimer’s-Training-Resveratrol (ADTRSV). RSV groups received 20 mg/kg/day orally. The aerobic exercise protocol consisted of treadmill running (6–18 m/min) five days per week for eight weeks. Hippocampal PINK1 and PARKIN expression levels were analyzed.
Results: AD induction significantly reduced PINK1 and PARKIN expression (P < 0.001). Compared to the AD group, significant increases in PINK1 and PARKIN were observed in the ADT (P = 0.043; P = 0.005), ADRSV (P = 0.033; P = 0.046), and ADTRSV (P < 0.001) groups. The ADTRSV group showed higher PINK1 expression than ADT (P = 0.036) and ADRSV (P = 0.046), and greater PARKIN expression than ADRSV (P = 0.046).
Conclusion: Exercise training and RSV supplementation improved hippocampal mitophagy in AD rats, with synergistic effects observed in the combined intervention. These findings suggest that non-pharmacological strategies may mitigate AD-related mitochondrial dysfunction.
References
1. Breijyeh Z, Karaman R. Comprehensive review on Alzheimer’s disease: Causes and treatment. Molecules. 2020;25(24):5789. [View at Publisher] [DOI] [PMID] [Google Scholar]
2. Xu Y, Zheng F, Zhong Q, Zhu Y. Ketogenic diet as a promising non-drug intervention for Alzheimer's disease: Mechanisms and clinical implications. J Alzheimers Dis . 2023;92(4):1173-98. [View at Publisher] [DOI] [PMID] [Google Scholar]
3. Papa S, Martino PL, Capitanio G, Gaballo A, De Rasmo D, Signorile A, et al. The oxidative phosphorylation system in mammalian mitochondria. Adv Exp Med Biol. 2012:942:3-37. [View at Publisher] [DOI] [PMID] [Google Scholar]
4. Garaeva AA, Kovaleva IE, Chumakov PM, Evstafieva AG. Mitochondrial dysfunction induces SESN 2 gene expression through activating transcription factor 4. Cell Cycle . 2016;15(1):64-71. [View at Publisher] [DOI] [PMID] [Google Scholar]
5. Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol. 2018;28(4):R170-R85. [View at Publisher] [DOI] [PMID] [Google Scholar]
6. Li X, Wu Z, Si X, Li J, Wu G, Wang M. The role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease and future strategies for targeted therapy. Eur J Med Res . 2025;30(1):434. [View at Publisher] [DOI] [PMID] [Google Scholar]
7. Wang S, Liao Z, Zhang Q, Han X, Liu C, Wang J. Mitochondrial dysfunction in Alzheimer's disease: a key frontier for future targeted therapies. Front Immunol . 2025:15:1484373. [View at Publisher] [DOI] [PMID] [Google Scholar]
8. Bar-Ziv R, Dutta N, Hruby A, Sukarto E, Averbukh M, Alcala A, et al. Glial-derived mitochondrial signals affect neuronal proteostasis and aging. Sci Adv. 2023;9(41):eadi1411. [View at Publisher] [DOI] [PMID] [Google Scholar]
9. Turner RS, Thomas RG, Craft S, Van Dyck CH, Mintzer J, Reynolds BA, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015;85(16):1383-91. [View at Publisher] [DOI] [PMID] [Google Scholar]
10. Van Acker ZP, Leroy T, Annaert W. Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases? Bioessays. 2025;47(1):e2400023. [View at Publisher] [DOI] [PMID] [Google Scholar]
11. Kang J, Liu M, Yang Q, Dang X, Li Q, Wang T, et al. Exercise training exerts beneficial effects on Alzheimer's disease through multiple signaling pathways. Front Aging Neurosci . 2025:17:1558078. [View at Publisher] [DOI] [PMID] [Google Scholar]
12. De la Rosa A, Olaso-Gonzalez G, Arc-Chagnaud C, Millan F, Salvador-Pascual A, García-Lucerga C, et al. Physical exercise in the prevention and treatment of Alzheimer's disease. J Sport Health Sci. 2020;9(5):394-404. [View at Publisher] [DOI] [PMID] [Google Scholar]
13. O'Reilly CL, Miller BF, Lewis Jr TL. Exercise and mitochondrial remodeling to prevent age-related neurodegeneration. J Appl Physiol (1985). 2023;134(1):181-9. [View at Publisher] [DOI] [PMID] [Google Scholar]
14. Chandra G, Kundu M, Rangasamy SB, Dasarathy S, Ghosh S, Watson R, et al. Increase in mitochondrial biogenesis in neuronal cells by RNS60, a physically-modified saline, via phosphatidylinositol 3-kinase-mediated upregulation of PGC1α. J Neuroimmune Pharmacol. 2018;13(2):143-62. [View at Publisher] [DOI] [PMID] [Google Scholar]
15. Puranik N, Kumari M, Tiwari S, Dhakal T, Song M. Resveratrol as a Therapeutic Agent in Alzheimer's Disease: Evidence from Clinical Studies. Nutrients. 2025;17(15):2557. [View at Publisher] [DOI] [PMID] [Google Scholar]
16. Rashet A, Abdi A, Barari A. Synergistic Role of Aerobic Training and Resveratrol on AMPK/PGC1-α/SIRT1 Pathway in the Hippocampus of Rats with Alzheimer's Disease. J Arch Mil Med. 2024;12(1):e144281. [View at Publisher] [DOI] [Google Scholar]
17. Iorio R, Celenza G, Petricca S. Mitophagy: molecular mechanisms, new concepts on Parkin activation and the emerging role of AMPK/ULK1 Axis. Cells. 2021;11(1):30. [View at Publisher] [DOI] [PMID] [Google Scholar]
18. Eslimi Esfehani D, Oryan S, Khosravi M, Valizadegan F. Effect of fennel extract on the improvement of memory disorders in beta amyloid alzheimer model of male wistar rats. J Ilam Univ Med Sci. 2019;27(1):1-12. [View at Publisher] [DOI] [Google Scholar]
19. Bedford TG, Tipton CM, Wilson NC, Oppliger RA, Gisolfi CV. Maximum oxygen consumption of rats and its changes with various experimental procedures. J Appl Physiol Respir Environ Exerc Physiol. 1979;47(6):1278-83. [View at Publisher] [DOI] [PMID] [Google Scholar]
20. Wu C, Yang L, Li Y, Dong Y, Yang B, Tucker LD, et al. Effects of exercise training on anxious-depressive-like behavior in Alzheimer rat. Med Sci Sports Exerc. 2020;52(7):1456-69. [View at Publisher] [DOI] [PMID] [Google Scholar]
21. Monserrat Hernández‐Hernández E, Serrano‐García C, Antonio Vázquez‐Roque R, Díaz A, Monroy E, Rodríguez‐Moreno A, et al. Chronic administration of resveratrol prevents morphological changes in prefrontal cortex and hippocampus of aged rats. Synapse. 2016;70(5):206-17. [View at Publisher] [DOI] [PMID] [Google Scholar]
22. Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 2019;22(3):401-12. [View at Publisher] [DOI] [PMID] [Google Scholar]
23. Castellazzi M, Patergnani S, Donadio M, Giorgi C, Bonora M, Bosi C, et al. Autophagy and mitophagy biomarkers are reduced in sera of patients with Alzheimer's disease and mild cognitive impairment. Sci Rep. 2019;9(1):20009. [View at Publisher] [DOI] [PMID] [Google Scholar]
24. Cicero AF, Ruscica M, Banach M. Resveratrol and cognitive decline: a clinician perspective. Arch Med Sci . 2019;15(4):936-43. [View at Publisher] [DOI] [PMID] [Google Scholar]
25. Pagar KR, Khandbahale SV, Phadtare DG. The therapeutic potential of resveratrol: a review of clinical trials. Asian J Pharm Res. 2019;9(3):193-9. [View at Publisher] [DOI] [Google Scholar]
26. Weidling IW, Swerdlow RH. Mitochondria in Alzheimer's disease and their potential role in Alzheimer's proteostasis. Exp Neurol. 2020;330:113321. [View at Publisher] [DOI] [PMID] [Google Scholar]
27. Han Y, Wang N, Kang J, Fang Y. β-Asarone improves learning and memory in Aβ 1-42-induced Alzheimer's disease rats by regulating PINK1-Parkin-mediated mitophagy. Metab Brain Dis. 2020;35:1109-17. [View at Publisher] [DOI] [PMID] [Google Scholar]
28. Sarraf SA, Sideris DP, Giagtzoglou N, Ni L, Kankel MW, Sen A, et al. PINK1/Parkin influences cell cycle by sequestering TBK1 at damaged mitochondria, inhibiting mitosis. Cell Rep. 2019;29(1):225-35.e5. [View at Publisher] [DOI] [PMID] [Google Scholar]
29. Chen L, Qin Y, Liu B, Gao M, Li A, Li X, et al. PGC-1 α-mediated mitochondrial quality control: molecular mechanisms and implications for heart failure. Front Cell Dev Biol. 2022:10:871357. [View at Publisher] [DOI] [PMID] [Google Scholar]
30. Zhao N, Yan Q-W, Xia J, Zhang X-L, Li B-X, Yin L-Y, et al. Treadmill exercise attenuates Aβ-induced mitochondrial dysfunction and enhances mitophagy activity in APP/PS1 transgenic mice. Neurochem Res. 2020;45(5):1202-14. [View at Publisher] [DOI] [PMID] [Google Scholar]
31. Rostamzadeh F, Najafipour H, Aminizadeh S, Jafari E. Therapeutic effects of the combination of moderate-intensity endurance training and MitoQ supplementation in rats with isoproterenol-induced myocardial injury: The role of mitochondrial fusion, fission, and mitophagy. Biomed Pharmacother. 2024;170:116020. [View at Publisher] [DOI] [PMID] [Google Scholar]
32. Pantiya P, Thonusin C, Chunchai T, Pintana H, Ongnok B, Nawara W, et al. Long-term lifestyle intervention is superior to transient modification for neuroprotection in D-galactose-induced aging rats. Life Sci. 2023;334:122248. [View at Publisher] [DOI] [PMID] [Google Scholar]
33. Khodagholi F, Zareh Shahamati S, Maleki Chamgordani M, Mousavi MA, Moslemi M, Salehpour M, et al. Interval aerobic training improves bioenergetics state and mitochondrial dynamics of different brain regions in restraint stressed rats. Mol Biol Rep. 2021;48(3):2071-82. [View at Publisher] [DOI] [PMID] [Google Scholar]
34. Zhao N, Zhang X, Li B, Wang J, Zhang C, Xu B. Treadmill exercise improves PINK1/Parkin-mediated mitophagy activity against Alzheimer's disease pathologies by upregulated SIRT1-FOXO1/3 axis in APP/PS1 mice. Mol Neurobiol. 2023;60(1):277-91. [View at Publisher] [DOI] [PMID] [Google Scholar]
35. Das S, Mitrovsky G, Vasanthi HR, Das DK. Antiaging properties of a grape-derived antioxidant are regulated by mitochondrial balance of fusion and fission leading to mitophagy triggered by a signaling network of Sirt1-Sirt3-Foxo3-PINK1-PARKIN. Oxid Med Cell Longev. 2014:2014:345105. [View at Publisher] [DOI] [PMID] [Google Scholar]
36. Li H, Qin S, Liang Q, Xi Y, Bo W, Cai M, et al. Exercise training enhances myocardial mitophagy and improves cardiac function via Irisin/FNDC5-PINK1/Parkin pathway in MI mice. Biomedicines. 2021;9(6):701. [View at Publisher] [DOI] [PMID] [Google Scholar]
37. Zhou J, Wang Z, He Y, Luo X, Zhang W, Yu L, et al. Qiliqiangxin reduced cardiomyocytes apotosis and improved heart function in infarcted heart through Pink1/Parkin-mediated mitochondrial autophagy. BMC Complement Med Ther. 2020;20(1):203. [View at Publisher] [DOI] [PMID] [Google Scholar]
38. Lee J, Hong S-W, Kwon H, Park SE, Rhee E-J, Park C-Y, et al. Resveratrol, an activator of SIRT1, improves ER stress by increasing clusterin expression in HepG2 cells. Cell Stress Chaperones. 2019;24(4):825-33. [View at Publisher] [DOI] [PMID] [Google Scholar]
39. Wang B, Ge S, Xiong W, Xue Z. Effects of resveratrol pretreatment on endoplasmic reticulum stress and cognitive function after surgery in aged mice. BMC Anesthesiol. 2018;18(1):141. [View at Publisher] [DOI] [PMID] [Google Scholar]
40. Li Y, Xu S, Giles A, Nakamura K, Lee JW, Hou X, et al. Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB J. 2011;25(5):1664. [View at Publisher] [DOI] [PMID] [Google Scholar]
41. Um J-H, Park S-J, Kang H, Yang S, Foretz M, McBurney MW, et al. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes. 2010;59(3):554-63. [View at Publisher] [DOI] [PMID] [Google Scholar]
42. Corpas R, Griñán-Ferré C, Rodríguez-Farré E, Pallàs M, Sanfeliu C. Resveratrol induces brain resilience against Alzheimer neurodegeneration through proteostasis enhancement. Mol Neurobiol. 2019;56(2):1502-16. [View at Publisher] [DOI] [PMID] [Google Scholar]
43. Solberg NO, Chamberlin R, Vigil JR, Deck LM, Heidrich JE, Brown DC, et al. Optical and SPION-Enhanced MR imaging shows that trans-stilbene inhibitors of NF-κB concomitantly lower alzheimer's disease plaque formation and microglial activation in AβPP/PS-1 transgenic mouse brain. J Alzheimers Dis. 2014;40(1):191-212. [View at Publisher] [DOI] [PMID] [Google Scholar]
44. Liao Z-Y, Chen J-L, Xiao M-H, Sun Y, Zhao Y-X, Pu D, et al. The effect of exercise, resveratrol or their combination on Sarcopenia in aged rats via regulation of AMPK/Sirt1 pathway. Exp Gerontol. 2017;98:177-83. [View at Publisher] [DOI] [PMID] [Google Scholar]
45. Broderick TL, Rasool S, Li R, Zhang Y, Anderson M, Al-Nakkash L, et al. Neuroprotective effects of chronic resveratrol treatment and exercise training in the 3xTg-AD mouse model of Alzheimer's disease. Int J Mol Sci. 2020;21(19):7337. [View at Publisher] [DOI] [PMID] [Google Scholar]
46. Benito-Cuesta I, Ordóñez-Gutiérrez L, Wandosell FJA. AMPK activation does not enhance autophagy in neurons in contrast to MTORC1 inhibition: different impact on β-amyloid clearance. Autophagy. 2021;17(3):656-71. [View at Publisher] [DOI] [PMID] [Google Scholar]
Send email to the article author
| Rights and permissions | |
 |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |