Relationship Between Nrf2/Keap1 and Exercise-Induced Modulation of Oxidative Stress in Hippocampal Tissue of Aged Diabetic Rats
محورهای موضوعی : Exercise Physiology and Performance
Safoura Alizade
1
,
Mohammad Faramarzi
2
1 - Department of Exercise Physiology, Faculty of Sport Sciences, University of Isfahan, Isfahan, Iran
2 - Department of Exercise Physiology, Faculty of Sport Sciences, University of Isfahan, Isfahan, Iran
کلید واژه: Nrf2/Keap1 Pathway, Diabetes, Endurance training, Resistance training, Aging ,
چکیده مقاله :
Introduction: Diabetes mellitus is a common metabolic disorder known for reducing antioxidant levels and concurrently increasing the production of free radicals. The Nrf2/Keap1/ARE signaling pathway may relate to insulin resistance in the brain. Exercise training may activate the production of reactive oxygen species (ROS) and boost antioxidant signaling pathways such as Nrf2/Keap1/ARE in the brain.
Methods: Fifteen male Wistar rats were divided into three groups: diabetic endurance training (DET, n=5), diabetic resistance training (DRT, n=5), and diabetic control (DC, n=5). Diabetes was induced using streptozotocin (30 mg/kg, i.p.) and a high-fat diet (55% fat, 31% carbohydrate, and 14% protein). The DET group underwent eight weeks of training at 75–60% of velocity at maximal oxygen uptake (vVO2max), while the DRT group performed resistance exercises at 60% of their maximum voluntary carrying capacity (MVCC), with the rats climbing a ladder 14–20 times per session, five days a week.
Results: In the DET group, Nrf2 expression correlated positively with MVCC3, whereas no significant correlations were found in the DRT group, and a negative correlation was observed in the DC group. Nrf2 and vVO2max showed a significant negative correlation at the second measurement (r = -0.728, P = 0.002), especially in the DC group (r = -0.85, P < 0.01). Keap1 levels exhibited weak to moderate positive correlations with vVO2max across groups and significant positive correlations with MVCC parameters, particularly in the DRT group (r = 0.92, p = 0.01).
Conclusion: The analysis revealed varying correlations between Nrf2 and Keap1 levels with exercise performance metrics (vVO2max and MVCC parameters), with significant relationships observed only in specific experimental groups, highlighting the need for further investigation into the differential effects of these proteins on exercise outcomes.
Introduction: Diabetes mellitus is a common metabolic disorder known for reducing antioxidant levels and concurrently increasing the production of free radicals. The Nrf2/Keap1/ARE signaling pathway may relate to insulin resistance in the brain. Exercise training may activate the production of reactive oxygen species (ROS) and boost antioxidant signaling pathways such as Nrf2/Keap1/ARE in the brain.
Methods: Fifteen male Wistar rats were divided into three groups: diabetic endurance training (DET, n=5), diabetic resistance training (DRT, n=5), and diabetic control (DC, n=5). Diabetes was induced using streptozotocin (30 mg/kg, i.p.) and a high-fat diet (55% fat, 31% carbohydrate, and 14% protein). The DET group underwent eight weeks of training at 75–60% of velocity at maximal oxygen uptake (vVO2max), while the DRT group performed resistance exercises at 60% of their maximum voluntary carrying capacity (MVCC), with the rats climbing a ladder 14–20 times per session, five days a week.
Results: In the DET group, Nrf2 expression correlated positively with MVCC3, whereas no significant correlations were found in the DRT group, and a negative correlation was observed in the DC group. Nrf2 and vVO2max showed a significant negative correlation at the second measurement (r = -0.728, P = 0.002), especially in the DC group (r = -0.85, P < 0.01). Keap1 levels exhibited weak to moderate positive correlations with vVO2max across groups and significant positive correlations with MVCC parameters, particularly in the DRT group (r = 0.92, p = 0.01).
Conclusion: The analysis revealed varying correlations between Nrf2 and Keap1 levels with exercise performance metrics (vVO2max and MVCC parameters), with significant relationships observed only in specific experimental groups, highlighting the need for further investigation into the differential effects of these proteins on exercise outcomes.
1. Ma, N. and Y. Zhang, Effects of resveratrol therapy on glucose metabolism, insulin resistance, inflammation, and renal function in the elderly patients with type 2 diabetes mellitus: A randomized controlled clinical trial protocol. Medicine, 2022. 101(32).
2. Pu, D., et al., Protective effects of sulforaphane on cognitive impairments and AD-like lesions in diabetic mice are associated with the upregulation of Nrf2 transcription activity. Neuroscience, 2018. 381: p. 35-45.
3. Bhatti, J.S., et al., Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives. Free Radical Biology and Medicine, 2022.
4. Tanwar, A., K. Gulati, and A. Ray, Neuroprotective Effect of Withania Somnifera Root Extract In Type 2 Diabetes Mellitus Induced Cognitive Impairment And Neurodegeneration In Rats. Asian Journal of Pharmaceutical Research and Development, 2022. 10(4): p. 47-54.
5. Kang, T.-C., Nuclear factor-erythroid 2-related factor 2 (Nrf2) and mitochondrial dynamics/mitophagy in neurological diseases. Antioxidants, 2020. 9(7): p. 617.
6. Lee, K.H., M. Cha, and B.H. Lee, Neuroprotective effect of antioxidants in the brain. International journal of molecular sciences, 2020. 21(19): p. 7152.
7. Liu, Y., J. Deng, and D. Fan, G-Rh4 improves pancreatic β-cells dysfunction in vivo and in vitro by increased expression of Nrf2 and its target genes. Food and Chemical Toxicology, 2021. 148: p. 111925.
8. Zweig, J.A., et al., Loss of NRF2 accelerates cognitive decline, exacerbates mitochondrial dysfunction, and is required for the cognitive enhancing effects of Centella asiatica during aging. Neurobiology of Aging, 2021. 100: p. 48-58.
9. Cai, M., et al., The Molecular Mechanisms of Excessive Hippocampal Endoplasmic Reticulum Stress Depressing Cognition-related Proteins Expression and the Regulatory Effects of Nrf2. Neuroscience, 2020. 431: p. 152-165.
10. Kasai, S., et al., Regulation of Nrf2 by mitochondrial reactive oxygen species in physiology and pathology. Biomolecules, 2020. 10(2): p. 320.
11. Wang, C., et al., Oxidative parameters in the rat brain of chronic mild stress model for depression: relation to anhedonia-like responses. The Journal of membrane biology, 2012. 245(11): p. 675-681.
12. Done, A.J. and T. Traustadóttir, Nrf2 mediates redox adaptations to exercise. Redox biology, 2016. 10: p. 191-199.
13. Tutakhail, A., et al., Induction of brain Nrf2-HO-1 pathway and antinociception after different physical training paradigms in mice. Life sciences, 2018. 209: p. 149-156.
14. Oakhill, J.S., et al., AMPK is a direct adenylate charge-regulated protein kinase. Science, 2011. 332(6036): p. 1433-1435.
15. Joo, M.S., et al., AMPK facilitates nuclear accumulation of Nrf2 by phosphorylating at serine 550. Molecular and cellular biology, 2016. 36(14): p. 1931-1942.
16. Done, A.J., et al., Exercise-induced Nrf2-signaling is impaired in aging. Free Radical Biology and Medicine, 2016. 96: p. 130-138.
17. Eynon, N., et al., Interaction between SNPs in the NRF2 gene and elite endurance performance. Physiological genomics, 2010. 41(1): p. 78-81.
18. Zhang, M., et al., The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Experimental diabetes research, 2008. 2008.
19. Liu, Z., et al., Antidiabetic effects of malonyl ginsenosides from Panax ginseng on type 2 diabetic rats induced by high-fat diet and streptozotocin. Journal of Ethnopharmacology, 2013. 145(1): p. 233-240.
20. Qian, C., et al., High-fat diet/low-dose streptozotocin-induced type 2 diabetes in rats impacts osteogenesis and Wnt signaling in bone marrow stromal cells. PLoS One, 2015. 10(8): p. e0136390.
21. de Bem, G.F., et al., Antidiabetic effect of Euterpe oleracea Mart.(açai) extract and exercise training on high-fat diet and streptozotocin-induced diabetic rats: A positive interaction. PLoS One, 2018. 13(6): p. e0199207.
22. Singulani, M.P., et al., Effects of strength training on osteogenic differentiation and bone strength in aging female Wistar rats. Scientific reports, 2017. 7: p. 42878.
23. Leandro, C.G., et al., A program of moderate physical training for Wistar rats based on maximal oxygen consumption. Journal of strength and conditioning research, 2007. 21(3): p. 751.
24. PITHON-CURI, T.N.C., Aprogram Of Moderate Physical Training For Wistar Rats Based On Maximal Oxygen Consumption. Journal of strength and conditioning research, 2007. 21(3): p. 000-000.
25. Nourshahi, M., et al., Effect of 8 weeks endurance training on serum vascular endothelial growth factor and endostatin in wistar rats. Koomesh, 2012. 13(4): p. 474-479.
26. Egbujor, M.C., et al., Activation of Nrf2 signaling pathway by natural and synthetic chalcones: A therapeutic road map for oxidative stress. Expert review of clinical pharmacology, 2021. 14(4): p. 465-480.
27. Yu, C. and J.-H. Xiao, The Keap1‐Nrf2 system: a mediator between oxidative stress and aging. Oxidative Medicine and Cellular Longevity, 2021. 2021(1): p. 6635460.
28. Tao, J., et al., Mind-body exercise improves cognitive function and modulates the function and structure of the hippocampus and anterior cingulate cortex in patients with mild cognitive impairment. NeuroImage: Clinical, 2019. 23: p. 101834.
29. Lane, M.T., et al., Endocrine responses and acute mTOR pathway phosphorylation to resistance exercise with leucine and whey. Biology of sport, 2017. 34(2): p. 197-203.
30. Schoenfeld, B.J., et al., Resistance training volume enhances muscle hypertrophy but not strength in trained men. Medicine and science in sports and exercise, 2019. 51(1): p. 94.
31. Rahimian, R., P. Cordeau Jr, and J. Kriz, Brain response to injuries: when microglia go sexist. Neuroscience, 2019. 405: p. 14-23.
32. Pedersen, B.K. and B. Saltin, Exercise as medicine–evidence for prescribing exercise as therapy in 26 different chronic diseases. Scandinavian journal of medicine & science in sports, 2015. 25: p. 1-72.
33. Liochev, S.I., Reactive oxygen species and the free radical theory of aging. Free radical biology and medicine, 2013. 60: p. 1-4.
34. Nemmar, A., et al., Exercise training mitigates water pipe smoke exposure-induced pulmonary impairment via inhibiting NF-κB and activating Nrf2 signalling pathways. Oxidative Medicine and Cellular Longevity, 2018. 2018.
35. Aranda, P., et al., High-protein diet induces oxidative stress in rat brain: protective action of high-intensity exercise against lipid peroxidation. Nutricion hospitalaria, 2015. 31(2): p. 866-874.
