Effect of Six Weeks of Treadmill Running on JAK1/STAT3 Pathway Gene Expression in the Basal Ganglia of Type-1 Diabetic Rats

Barzegaran, Mozhdeh; Fallah Mohammadi, Ziya; Akbari, Aboalfazl

doi:10.22059/jsb.2023.357588.1583

Document Type : Research Paper I Open Access I Released under CC BY-NC 4.0 license

Authors

¹ Department of Exercise Physiology, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Iran

² Corresponding Author, Department of Exercise Physiology, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Iran.

https://doi.org/10.22059/jsb.2023.357588.1583

Abstract

Introduction: The JAK/STAT signaling pathway is an important pathway used by cytokines and its excessive activation can lead to various diseases. This signaling pathway is essential for normal homeostasis. Dysregulation of this pathway contributes to the development of obesity and diabetes. This study aimed to investigate the effect of six weeks of endurance running exercises on the gene expression of the JAK1/STAT3 pathway in the basal ganglia of diabetic rats.
Methods: In this experimental study, 40 male rats were randomly divided into four equal Healthy, Exercise, Diabetes, and Diabetes + Exercise groups. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg body weight). The incremental endurance exercise program was gradually implemented for six weeks, and five sessions per week. The first week started with a speed of 10 m/min for 10 minutes, and by the sixth week, it reached a speed of 18 m/min for 30 minutes. Forty-eight hours after the last exercise session, the rats were anesthetized and the brain tissue was removed from the skull to extract the basal ganglia. The extracted tissue was used to measure gene expression by the qPCR method. One-way ANOVA and LSD post hoc test were used to check the between-group differences. The significance level was considered smaller than 0.05.
Results: Type-1 diabetes induction did not change JAK1/STAT3 gene expression in basal ganglia (P>0.05). The endurance exercise program decreased the gene expression values of JAK1 (P=0.009) and STAT3 (P=0.002) compared to the diabetes group. This decrease had a similar process for both genes.
Conclusion: In the present study, six weeks of endurance running on the treadmill with moderate intensity decreased the gene expression of the JAK1/STAT3 pathway. Therefore, this exercise protocol can be suggested as a non-pharmacological tool without side effects to inhibit this pathway in diabetes to protect basal ganglia neurons.

Keywords

References

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[25] Allen Reish HE, Standaert DG. Role of α-synuclein in inducing innate and adaptive immunity in Parkinson disease. Journal of Parkinson's disease. 2015;5(1):1-19. doi: 10.3233/JPD-140491.

[26] Xin P, Xu X, Deng C, Liu S, Wang Y, Zhou X, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. International immunopharmacology. 2020;80:106210. doi: 10.1016/j.intimp.2020.106210.

[27] O'Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity. 2012;36(4):542-50. doi: 10.1016/j.immuni.2012.03.014.

[28] O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311-28. doi: 10.1146/annurev-med-051113-024537.

[29] Rinder MR, Miller TR, Ehsani AA. Effects of endurance exercise training on left ventricular systolic performance and ventriculoarterial coupling in patients with coronary artery disease. American heart journal. 1999;138(1):169-74. doi: 10.1016/s0002-8703(99)70264-4.

[30] Aly YE, Abdou AS, Rashad MM, Nassef MM. Effect of exercise on serum vitamin D and tissue vitamin D receptors in experimentally induced type 2 Diabetes Mellitus. Journal of advanced research. 2016;7(5):671-9. doi: 10.1016/j.jare.2016.07.001.

[31] Sticka KD, Schnurr TM, Jerome SP, Dajles A, Reynolds AJ, Duffy LK, et al. Exercise increases glucose transporter-4 levels on peripheral blood mononuclear cells. Medicine and science in sports and exercise. 2018;50(5):938-44. Doi: 10.1249/MSS.0000000000001528.

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[33] Zar A, Ahmadi F, Karimi F, Ahmadi M, Ramsbottom R. Effect of Resistance Training and Spirulina platensis on Expression of IL-6, Gp130 Cytokines, JAK-STAT Signaling in Male Rats Skeletal Muscle. Molecular & Cellular Biomechanics. 2022;19(1):51-59. Doi.org/10.32604/mcb.2022.018345

[34] Kurd M, Valipour Dehnou V, Tavakoli SA, Gahreman DE. Effects of endurance training on hippocampus DJ‐1, cannabinoid receptor type 2 and blood glucose concentration in diabetic rats. Journal of Diabetes Investigation. 2019;10(1):43-50. Doi: 10.1111/jdi.12868.

[35] Jelodar G, Mohammadi M, Akbari A, Nazifi S. Cyclohexane extract of walnut leaves improves indices of oxidative stress, total homocysteine and lipids profiles in streptozotocin‐induced diabetic rats. Physiological reports. 2020;8(1):e14348. Doi: 10.14814/phy2.14348

[36] Amin MN, El-Mowafy M, Mobark A, Abass N, Elgaml A. Exercise-induced downregulation of serum interleukin-6 and tumor necrosis factor-alpha in Egyptian handball players. Saudi Journal of Biological Sciences. 2021;28(1):724-30. Doi: 10.1016/j.sjbs.2020.10.065

[37] Musi N, Fujii N, Hirshman MF, Ekberg I, Froberg S, Ljungqvist O, et al. AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise. Diabetes. 2001;50(5):921-7. Dio:10.2337/diabetes.50.5.921.

[38] Park S, Lee H-J, Jeong S-J, Song HS, Kim M, Lee H-J, et al. Inhibition of JAK1/STAT3 signaling mediates compound K-induced apoptosis in human multiple myeloma U266 cells. Food and chemical toxicology. 2011;49(6):1367-72. doi: 10.1016/j.fct.2011.03.021.

[39] Fan J, Chen Q, Wei L, Zhou X, Wang R, Zhang H. Asiatic acid ameliorates CCl4-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways. Drug Design, Development and Therapy. 2018:3595-605. doi: 10.2147/DDDT.S179876

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[42] Da Silva FC, da Rosa Iop R, Andrade A, Costa VP, Gutierres Filho PJB, da Silva R. Effects of physical exercise on the expression of MicroRNAs: a systematic review. The Journal of Strength & Conditioning Research. 2020;34(1):270-80. doi: 10.1519/JSC.0000000000003103.

[43] Sarwar A, Wang B, Su Q, Zhang Y. MiRNAs directly targeting the key intermediates of biological pathways in pancreatic cancer. Biochemical Pharmacology. 2021;189:114357. doi: 10.1016/j.bcp.2020.114357

[44] Ostovar M, Akbari A, Anbardar MH, Iraji A, Salmanpour M, Ghoran SH, et al. Effects of Citrullus colocynthis L. in a rat model of diabetic neuropathy. Journal of Integrative Medicine. 2020;18(1):59-67. doi: 10.1016/j.joim.2019.12.002.

[45] Najafi R, Hosseini A, Ghaznavi H, Mehrzadi S, Sharifi AM. Neuroprotective effect of cerium oxide nanoparticles in a rat model of experimental diabetic neuropathy. Brain Research Bulletin. 2017;131:117-22. doi: 10.1016/j.brainresbull.2017.03.013.

[46] Akbari A, Jelodar G, Nazifi S. The proposed mechanisms of radio frequency waves (RFWs) on nervous system functions impairment. Comparative Clinical Pathology. 2016;25:1289-301. doi.org/10.1007/s00580-015-2096-x

[47] Akbari A, Jelodar G, Nazifi S, Sajedianfard J. An overview of the characteristics and function of vitamin C in various tissues: relying on its antioxidant function. 2016;18(11):e4037. doi.org/10.17795/zjrms-4037. (In presian)

[48] Hebenstreit D, Horejs-Hoeck J, Duschl A. JAK/STAT-dependent gene regulation by cytokines. Drug news & perspectives. 2005;18(4):243-9. doi: 10.1358/dnp.2005.18.4.908658.

[49] Shuai K. Regulation of cytokine signaling pathways by PIAS proteins. Cell research. 2006;16(2):196-202. doi: 10.1038/sj.cr.7310027.

[50] Krebs DL, Hilton DJ. SOCS proteins: negative regulators of cytokine signaling. Stem cells. 2001;19(5):378-87. doi.org/10.1634/stemcells.19-5-378

[51] Harrison DA. The Jak/STAT pathway. Cold Spring Harbor perspectives in biology. 2012;4(3):1-4. doi: 10.1101/cshperspect.a011205.

Effect of Six Weeks of Treadmill Running on JAK1/STAT3 Pathway Gene Expression in the Basal Ganglia of Type-1 Diabetic Rats

References

References

[1] Gurzov EN, Stanley WJ, Pappas EG, Thomas HE, Gough DJ. The JAK/STAT pathway in obesity and diabetes. The FEBS Journal. 2016;283(16):3002-15. doi: 10.1111/febs.13709.

[2] Al-Rasheed NM, Al-Rasheed NM, Hasan IH, Al-Amin MA, Al-Ajmi HN, Mahmoud AM. Sitagliptin attenuates cardiomyopathy by modulating the JAK/STAT signaling pathway in experimental diabetic rats. Drug design, development and therapy. 2016:2095-107. doi: 10.2147/DDDT.S109287.

[3] Peer ME, Fallahmohammadi Z, Akbari A. The effect of progressive endurance training and extract of black winter truffle on proteins levels and expression of hippocampus α-synuclein and HSF1 in the healthy and diabetic rats. Metabolism Open. 2023;17:100232.doi: 10.1016/j.metop.2023.100232.

[5] Moshapa FT, Riches-Suman K, Palmer TM. Therapeutic targeting of the proinflammatory IL-6-JAK/STAT signalling pathways responsible for vascular restenosis in type 2 diabetes mellitus. Cardiology research and practice. 2019;2019:9846312-27. doi: 10.1155/2019/9846312.

[6] Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunological reviews. 2009;228(1):273-87. doi: 10.1111/j.1600-065X.2008.00754.x.

[7] Yan Z, Gibson SA, Buckley JA, Qin H, Benveniste EN. Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases. Clinical immunology (Orlando, Fla). 2018;189:4-13. doi: 10.1016/j.clim.2016.09.014.

[8] Hu X, li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduction and Targeted Therapy. 2021;6(1):402-35. doi.org/10.1038/s41392-021-00791-1

[9] Moresi V, Adamo S, Berghella L. The JAK/STAT pathway in skeletal muscle pathophysiology. Frontiers in physiology. 2019;10:500-10. doi.org/10.3389/fphys.2019.00500

[10] Zhang M, Zhou L, Xu Y, Yang M, Xu Y, Komaniecki GP, et al. A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis. Nature. 2020;586(7829):434-9. doi: 10.1038/s41586-020-2799-2.

[11] Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nature medicine. 2005;11(12):1314-21. doi: 10.1038/nm1325.

[12] Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. The Journal of Immunology. 2009;182(8):4499-506. doi: 10.4049/jimmunol.0802740.

[13] Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, et al. Targeting cancer stem cell pathways for cancer therapy. Signal transduction and targeted therapy. 2020;5(1):8-43. doi.org/10.1038/s41392-020-0110-5

[14] Zhang HF, Lai R. STAT3 in Cancer-Friend or Foe? Cancers. 2014;6(3):1408-40. doi: 10.3390/cancers6031408.

[15] Wang H-Q, Man Q-W, Huo F-Y, Gao X, Lin H, Li S-R, et al. STAT3 pathway in cancers: Past, present, and future. MedComm. 2022;3(2):e124. doi: 10.1002/mco2.124.

[16] Shao F, Pang X, Baeg GH. Targeting the JAK/STAT signaling pathway for breast cancer. Current medicinal chemistry. 2021;28(25):5137-51. doi: 10.2174/0929867328666201207202012.

[17] Jain M, Singh MK, Shyam H, Mishra A, Kumar S, Kumar A, et al. Role of JAK/STAT in the Neuroinflammation and its Association with Neurological Disorders. Annals of neurosciences. 2021;28(3-4):191-200. doi: 10.1177/09727531211070532.

[18] Biosa A, Outeiro TF, Bubacco L, Bisaglia M. Diabetes Mellitus as a Risk Factor for Parkinson's Disease: a Molecular Point of View. Mol Neurobiol. 2018;55(11):8754-63. doi: 10.1007/s12035-018-1025-9.

[19] Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, et al. Aggregated α‐synuclein activates microglia: a process leading to disease progression in Parkinson's disease. The FASEB Journal. 2005;19(6):533-42. doi: 10.1096/fj.04-2751com.

[20] Béraud D, Maguire-Zeiss KA. Misfolded α-synuclein and toll-like receptors: therapeutic targets for Parkinson's disease. Parkinsonism & related disorders. 2012;18:S17-S20. doi:10.1016/S1353-8020(11)70008-6

[21] Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W, et al. Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia. Glia. 2013;61(3):349-60. doi: 10.1002/glia.22437.

[22] McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia are positive for HLA‐DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology. 1988;38(8):1285-91. doi: 10.1212/wnl.38.8.1285.

[23] Lecours C, Bordeleau M, Cantin L, Parent M, Paolo TD, Tremblay M. Microglial Implication in Parkinson's Disease: Loss of Beneficial Physiological Roles or Gain of Inflammatory Functions? Frontiers in cellular neuroscience. 2018;12:282-90. doi.org/10.3389/fncel.2018.00282

[24] Moehle MS, West AB. M1 and M2 immune activation in Parkinson’s disease: foe and ally? Neuroscience. 2015;302:59-73. doi: 10.1016/j.neuroscience.2014.11.018.

[25] Allen Reish HE, Standaert DG. Role of α-synuclein in inducing innate and adaptive immunity in Parkinson disease. Journal of Parkinson's disease. 2015;5(1):1-19. doi: 10.3233/JPD-140491.

[26] Xin P, Xu X, Deng C, Liu S, Wang Y, Zhou X, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. International immunopharmacology. 2020;80:106210. doi: 10.1016/j.intimp.2020.106210.

[27] O'Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity. 2012;36(4):542-50. doi: 10.1016/j.immuni.2012.03.014.

[28] O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311-28. doi: 10.1146/annurev-med-051113-024537.

[29] Rinder MR, Miller TR, Ehsani AA. Effects of endurance exercise training on left ventricular systolic performance and ventriculoarterial coupling in patients with coronary artery disease. American heart journal. 1999;138(1):169-74. doi: 10.1016/s0002-8703(99)70264-4.

[30] Aly YE, Abdou AS, Rashad MM, Nassef MM. Effect of exercise on serum vitamin D and tissue vitamin D receptors in experimentally induced type 2 Diabetes Mellitus. Journal of advanced research. 2016;7(5):671-9. doi: 10.1016/j.jare.2016.07.001.

[31] Sticka KD, Schnurr TM, Jerome SP, Dajles A, Reynolds AJ, Duffy LK, et al. Exercise increases glucose transporter-4 levels on peripheral blood mononuclear cells. Medicine and science in sports and exercise. 2018;50(5):938-44. Doi: 10.1249/MSS.0000000000001528.

[33] Zar A, Ahmadi F, Karimi F, Ahmadi M, Ramsbottom R. Effect of Resistance Training and Spirulina platensis on Expression of IL-6, Gp130 Cytokines, JAK-STAT Signaling in Male Rats Skeletal Muscle. Molecular & Cellular Biomechanics. 2022;19(1):51-59. Doi.org/10.32604/mcb.2022.018345

[34] Kurd M, Valipour Dehnou V, Tavakoli SA, Gahreman DE. Effects of endurance training on hippocampus DJ‐1, cannabinoid receptor type 2 and blood glucose concentration in diabetic rats. Journal of Diabetes Investigation. 2019;10(1):43-50. Doi: 10.1111/jdi.12868.

[35] Jelodar G, Mohammadi M, Akbari A, Nazifi S. Cyclohexane extract of walnut leaves improves indices of oxidative stress, total homocysteine and lipids profiles in streptozotocin‐induced diabetic rats. Physiological reports. 2020;8(1):e14348. Doi: 10.14814/phy2.14348

[36] Amin MN, El-Mowafy M, Mobark A, Abass N, Elgaml A. Exercise-induced downregulation of serum interleukin-6 and tumor necrosis factor-alpha in Egyptian handball players. Saudi Journal of Biological Sciences. 2021;28(1):724-30. Doi: 10.1016/j.sjbs.2020.10.065

[37] Musi N, Fujii N, Hirshman MF, Ekberg I, Froberg S, Ljungqvist O, et al. AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise. Diabetes. 2001;50(5):921-7. Dio:10.2337/diabetes.50.5.921.

[38] Park S, Lee H-J, Jeong S-J, Song HS, Kim M, Lee H-J, et al. Inhibition of JAK1/STAT3 signaling mediates compound K-induced apoptosis in human multiple myeloma U266 cells. Food and chemical toxicology. 2011;49(6):1367-72. doi: 10.1016/j.fct.2011.03.021.

[39] Fan J, Chen Q, Wei L, Zhou X, Wang R, Zhang H. Asiatic acid ameliorates CCl4-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways. Drug Design, Development and Therapy. 2018:3595-605. doi: 10.2147/DDDT.S179876

[42] Da Silva FC, da Rosa Iop R, Andrade A, Costa VP, Gutierres Filho PJB, da Silva R. Effects of physical exercise on the expression of MicroRNAs: a systematic review. The Journal of Strength & Conditioning Research. 2020;34(1):270-80. doi: 10.1519/JSC.0000000000003103.

[43] Sarwar A, Wang B, Su Q, Zhang Y. MiRNAs directly targeting the key intermediates of biological pathways in pancreatic cancer. Biochemical Pharmacology. 2021;189:114357. doi: 10.1016/j.bcp.2020.114357

[44] Ostovar M, Akbari A, Anbardar MH, Iraji A, Salmanpour M, Ghoran SH, et al. Effects of Citrullus colocynthis L. in a rat model of diabetic neuropathy. Journal of Integrative Medicine. 2020;18(1):59-67. doi: 10.1016/j.joim.2019.12.002.

[45] Najafi R, Hosseini A, Ghaznavi H, Mehrzadi S, Sharifi AM. Neuroprotective effect of cerium oxide nanoparticles in a rat model of experimental diabetic neuropathy. Brain Research Bulletin. 2017;131:117-22. doi: 10.1016/j.brainresbull.2017.03.013.

[46] Akbari A, Jelodar G, Nazifi S. The proposed mechanisms of radio frequency waves (RFWs) on nervous system functions impairment. Comparative Clinical Pathology. 2016;25:1289-301. doi.org/10.1007/s00580-015-2096-x

[47] Akbari A, Jelodar G, Nazifi S, Sajedianfard J. An overview of the characteristics and function of vitamin C in various tissues: relying on its antioxidant function. 2016;18(11):e4037. doi.org/10.17795/zjrms-4037. (In presian)

[48] Hebenstreit D, Horejs-Hoeck J, Duschl A. JAK/STAT-dependent gene regulation by cytokines. Drug news & perspectives. 2005;18(4):243-9. doi: 10.1358/dnp.2005.18.4.908658.

[49] Shuai K. Regulation of cytokine signaling pathways by PIAS proteins. Cell research. 2006;16(2):196-202. doi: 10.1038/sj.cr.7310027.

[50] Krebs DL, Hilton DJ. SOCS proteins: negative regulators of cytokine signaling. Stem cells. 2001;19(5):378-87. doi.org/10.1634/stemcells.19-5-378

[51] Harrison DA. The Jak/STAT pathway. Cold Spring Harbor perspectives in biology. 2012;4(3):1-4. doi: 10.1101/cshperspect.a011205.

Volume 15, Issue 2 - Serial Number 96May 2023Pages 29-41

Volume 15, Issue 2 - Serial Number 96
May 2023
Pages 29-41