The effect of high-intensity interval training on the expressions of CHOP and ATF6 in liver tissue in rats with type 2 diabetes

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

Authors

1 Department of Physical Education and Sports Science, Science and Research branch, Islamic Azad University, Tehran, Iran.

2 Associate Professor, Department of Physical Education and Sports Sciences, Faculty of Literature, Humanities and Social Sciences, Science and Research Unit, Islamic Azad University, Tehran, Iran

3 Department of Sports Physiology, Faculty of Physical Education, Kharazmi University, Tehran, Iran

4 Assistant Professor, Department of Physical Education and Sport Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran

Abstract

Aim:   Type 2 diabetes is a complex metabolic disorder characterized by insulin resistance and glucose dysregulation. It is a major concern of the World Health Organization, affecting millions of people worldwide. The purpose of this study was to investigate the effect of  8 weeks of high-intensity interval training on the expression of activating transcription factor-6 (ATF-6) and C/EBP homologue (CHOP) proteins in liver tissue in rats with type 2 diabetes. Method:  The current study was experimental with a post-test design with a control group. A number of 24 Wistar male rats, aged 6 weeks and weighing approximately 200-250 grams, were obtained from the Pasteur Institute of Iran. Rats were randomly divided into 3 groups of 8 high intensity interval training (HIIT) diabetic, diabetic control and healthy control. The training groups performed 5 HIIT training sessions on the treadmill during 8 weeks and each week (the training protocol was 8 weeks of interval training, 5 sessions per week with intense 2-minute intervals with 2-8 repetitions and 80-90 The percentage of maximum running speed and 1-minute rest intervals were performed with 50-56% of maximum running speed. After 48 hours from the last training session and after fasting days, all rats were anesthetized and liver tissue was harvested. The data were analyzed by one-way analysis of variance (ANOVA).Results: The results showed that ATF-6 protein levels in type 2 diabetic male rats did not change significantly after 8 weeks of high-intensity interval training (P = 0.73). But CHOP protein levels showed a significant increase after 8 weeks (P = 0.001). CHOP protein levels in the diabetic training group showed a non-significant decrease compared to the diabetic control group (P < 0.05), but in the diabetic training group compared to the healthy control group, it showed a significant increase (P = 0.001).  Conclusion: As a result, 8 weeks of high-intensity interval training can have beneficial effects on reducing endoplasmic reticulum stress in liver tissue caused by type 2 diabetes in diabetic rats. Furthermore, further research is needed to confirm these findings and explore the potential mechanisms involved.

Keywords

Main Subjects

References

  1. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, Hu FB, Kahn CR, Raz I, Shulman GI, Simonson DC. Type 2 diabetes mellitus. Nature reviews Disease primers. 2015 Jul 23;1(1):1-22.
  2. Jaacks LM, Siegel KR, Gujral UP, Narayan KV. Type 2 diabetes: A 21st century epidemic. Best Practice & Research Clinical Endocrinology & Metabolism. 2016 Jun 1;30(3):331-43.
  3. Shrestha P, Ghimire L. A review about the effect of life style modification on diabetes and quality of life. Global journal of health science. 2012 Nov;4(6):185.
  4. Balasubramanyam M, Lenin R, Monickaraj F. Endoplasmic reticulum stress in diabetes: New insights of clinical relevance. Indian journal of clinical biochemistry. 2010 Apr;25:111-8.
  5. Vitale, A., Ceriotti, A., & Denecke, J. (1993). The role of the endoplasmic reticulum in protein synthesis, modification and intracellular transport. Journal of Experimental Botany, 44(9), 1417-1444.
  6. Gregor MF, Hotamisligil GS. Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. Journal of lipid research. 2007 Sep 1;48(9):1905-14.
  7. Promlek T, Ishiwata-Kimata Y, Shido M, Sakuramoto M, Kohno K, Kimata Y. Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways. Molecular biology of the cell. 2011 Sep 15;22(18):3520-32.
  8. Adachi Y, Yamamoto K, Okada T, Yoshida H, Harada A, Mori K. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell structure and function. 2008;33(1):75-89.
  9. Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M, Mori K. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Molecular and cellular biology. 2000 Sep 1;20(18):6755-67.
  10. Hu H, Tian M, Ding C, Yu S. The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Frontiers in immunology. 2019 Jan 4; 9:3083.
  11. Kim HM, Lee ES, Lee BR, Yadav D, Kim YM, Ko HJ, Park KS, Lee EY, Chung CH. CC chemokine receptor 2 inhibitor ameliorates hepatic steatosis by improving ER stress and inflammation in a type 2 diabetic mouse model. PloS one. 2015 Mar 27;10(3):e0120711.
  12. Gupta D, B Krueger C, Lastra G. Over-nutrition, obesity and insulin resistance in the development of β-cell dysfunction. Current diabetes reviews. 2012 Mar 1;8(2):76-83.
  13. Postic C, Dentin R, Girard J. Role of the liver in the control of carbohydrate and lipid homeostasis. Diabetes & metabolism. 2004 Nov 1;30(5):398-408.
  14. Wang Y, Guo Y, Xu Y, Wang W, Zhuang S, Wang R, Xiao W. HIIT Ameliorates Inflammation and Lipid Metabolism by Regulating Macrophage Polarization and Mitochondrial Dynamics in the Liver of Type 2 Diabetes Mellitus Mice. Metabolites. 2022 Dec 21;13(1):14.
  15. Gibala MJ. Functional high‐intensity training: A HIT to improve insulin sensitivity in type 2 diabetes. Experimental Physiology. 2018 Jul;103(7):937-8.
  16. Cassidy S, Thoma C, Houghton D, Trenell MI. High-intensity interval training: a review of its impact on glucose control and cardiometabolic health. Diabetologia. 2017 Jan;60(1):7-23.
  17. Matsunaga S, Yamada T, Mishima T, Sakamoto M, Sugiyama M, Wada M. Effects of high-intensity training and acute exercise on in vitro function of rat sarcoplasmic reticulum. European journal of applied physiology. 2007 Apr;99:641-9.
  18. Afravi N, Abednatanzi H, Helalizade M, Gholami M. The Effect of High-Intensity Interval Training (HIIT) and Thyme Extract on P53 Gene Expression in Liver Tissue and Insulin Resistance in Type 2 Diabetic Rats. Razi Journal of Medical Sciences. 2023;29(11):346-361.
  19. Durrer C, Francois M, Neudorf H, Little JP. Acute high-intensity interval exercise reduces human monocyte Toll-like receptor 2 expression in type 2 diabetes. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2017 Apr 1;312(4):R529-38.
  20. Hariri N, Thibault L. High-fat diet-induced obesity in animal models. Nutrition research reviews. 2010 Dec;23(2):270-99.
  21. Zhang M, Lv XY, Li J, Xu ZG, Chen L. The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Journal of Diabetes Research. 2008 Jan 1;2008.
  22. Bedford TG, Tipton CM, Wilson NC, Oppliger RA, Gisolfi CV. Maximum oxygen consumption of rats and its changes with various experimental procedures. Journal of Applied Physiology. 1979 Dec 1;47(6):1278-83.
  23. Afzalpour ME, Chadorneshin HT, Foadoddini M, Eivari HA. Comparing interval and continuous exercise training regimens on neurotrophic factors in rat brain. Physiology & behavior. 2015 Aug 1;147:78-83.
  24. Junior N. DNA and RNA stabilization. Protocols. io. 2020 May 14.
  25. Scicchitano MS, Dalmas DA, Boyce RW, Thomas HC, Frazier KS. Protein extraction of formalin-fixed, paraffin-embedded tissue enables robust proteomic profiles by mass spectrometry. Journal of Histochemistry & Cytochemistry. 2009 Sep;57(9):849-60.
  26. Scicchitano MS, Dalmas DA, Boyce RW, Thomas HC, Frazier KS. Protein extraction of formalin-fixed, paraffin-embedded tissue enables robust proteomic profiles by mass spectrometry. Journal of Histochemistry & Cytochemistry. 2009 Sep;57(9):849-60.
  27. Riek AE, Oh J, Sprague JE, Timpson A, De Las Fuentes L, Bernal-Mizrachi L, Schechtman KB, Bernal-Mizrachi C. Vitamin D suppression of endoplasmic reticulum stress promotes an antiatherogenic monocyte/macrophage phenotype in type 2 diabetic patients. Journal of Biological Chemistry. 2012 Nov 9;287(46):38482-94.
  28. Ruan L, Li F, Li S, Zhang M, Wang F, Lv X, Liu Q. Effect of different exercise intensities on hepatocyte apoptosis in HFD-induced NAFLD in rats: the possible role of endoplasmic reticulum stress through the regulation of the IRE1/JNK and eIF2α/CHOP signal pathways. Oxidative Medicine and Cellular Longevity. 2021 Mar 15;2021.
  29. Yuan Z, Xiao-Wei L, Juan W, Xiu-Juan L, Nian-Yun Z, Lei S. HIIT and MICT attenuate high-fat diet-induced hepatic lipid accumulation and ER stress via the PERK-ATF4-CHOP signaling pathway. Journal of physiology and biochemistry. 2022 Aug;78(3):641-52.
  30. Delfan M, Delphan M, Kordi MR, Ravasi AA, Safa M, Gorgani-Firuzjaee S, Fatemi A, Bandarian F, Nasli-Esfahani E. High intensity interval training improves diabetic cardiomyopathy via miR-1 dependent suppression of cardiomyocyte apoptosis in diabetic rats. Journal of Diabetes & Metabolic Disorders. 2020 Jun;19:145-52.
  31. Böhm A, Weigert C, Staiger H, Häring HU. Exercise and diabetes: relevance and causes for response variability. Endocrine. 2016 Mar;51:390-401.
  32. Wang M. Reducing stress-induced CHOP is renoprotective. Nature Reviews Nephrology. 2021 Nov;17(11):707
  33. Chengji W, Xianjin F. Exercise protects against diabetic cardiomyopathy by the inhibition of the endoplasmic reticulum stress pathway in rats. Journal of cellular physiology. 2019 Feb;234(2):1682-8.
  34. Hetz C, Martinon F, Rodriguez D, Glimcher LH. The unfolded protein response: integrating stress signals through the stress sensor IRE1α. Physiological reviews. 2011 Oct;91(4):1219-43.
  35. Chikka MR, McCabe DD, Tyra HM, Rutkowski DT. C/EBP homologous protein (CHOP) contributes to suppression of metabolic genes during endoplasmic reticulum stress in the liver. Journal of biological chemistry. 2013 Feb 1;288(6):4405-15.
  36. Ariyama Y, Tanaka Y, Shimizu H, Shimomura K, Okada S, Saito T, Yamada E, Oyadomari S, Mori M, Mori M. The role of CHOP messenger RNA expression in the link between oxidative stress and apoptosis. Metabolism. 2008 Dec 1;57(12):1625-35.
  37. Estébanez B, De Paz JA, Cuevas MJ, González-Gallego J. Endoplasmic reticulum unfolded protein response, aging and exercise: An update. Frontiers in Physiology. 2018 Dec 5;9:1744.
  38. Papageorgiou CD, Stamatopoulos VP, Samaras CD, Statharakos NS, Papageorgiou ED, Dzhambazova EB. Hormesis-like benefits of physical exercises due to increased reactive oxygen species. Phys. Educ. Sport. Kinesither. Res. J. 2016;1:76-84.
  39. Khadir A, Kavalakatt S, Abubaker J, Cherian P, Madhu D, Al-Khairi I, Abu-Farha M, Warsame S, Elkum N, Dehbi M, Tiss A. Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone. Metabolism. 2016 Sep 1;65(9):1409-20.
  40. Song YH, Li Y, Du J, Mitch WE, Rosenthal N, Delafontaine P. Muscle-specific expression of IGF-1 blocks angiotensin II–induced skeletal muscle wasting. The Journal of clinical investigation. 2005 Feb 1;115(2):451-8.
  41. Li J, Huang L, Xiong W, Gu C, Zhang S, Xue X. Effect of aerobic exercise on GRP78 and ATF6 expressions in mice with non-alcoholic fatty liver disease. Sports Medicine and Health Science. 2023 Jun 1;5(2):112-9.
  42. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. science. 2011 Nov 25;334(6059):1081-6.
  43. Oka OB, Pierre AS, Pringle MA, Tungkum W, Cao Z, Fleming B, Bulleid NJ. Activation of the UPR sensor ATF6α is regulated by its redox-dependent dimerization and ER retention by ERp18. Proceedings of the National Academy of Sciences. 2022 Mar 22;119(12):e2122657119.
  44. Thuerauf DJ, Morrison L, Glembotski CC. Opposing roles for ATF6α and ATF6β in endoplasmic reticulum stress response gene induction. Journal of Biological Chemistry. 2004 May 14;279(20):21078-84.
  45. Adachi Y, Yamamoto K, Okada T, Yoshida H, Harada A, Mori K. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell structure and function. 2008;33(1):75-89.
  46. Madhusudhan T, Wang H, Dong W, Ghosh S, Bock F, Thangapandi VR, Ranjan S, Wolter J, Kohli S, Shahzad K, Heidel F. Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy. Nature communications. 2015 Mar 10;6(1):6496.
  47. Kitakaze K, Oyadomari M, Zhang J, Hamada Y, Takenouchi Y, Tsuboi K, Inagaki M, Tachikawa M, Fujitani Y, Okamoto Y, Oyadomari S. ATF4-mediated transcriptional regulation protects against β-cell loss during endoplasmic reticulum stress in a mouse model. Molecular Metabolism. 2021 Dec 1;54:101338.
  48. Oka OB, van Lith M, Rudolf J, Tungkum W, Pringle MA, Bulleid NJ. ER p18 regulates activation of ATF 6α during unfolded protein response. The EMBO journal. 2019 Aug 1;38(15):e100990.
  49. Mustapha S, Mohammed M, Azemi AK, Jatau AI, Shehu A, Mustapha L, Aliyu IM, Danraka RU, Amin A, Bala AA, Ahmad WA. Current status of endoplasmic reticulum stress in type II diabetes. Molecules. 2021 Jul 19;26(14):4362.
  50. Tiwari S, Kaur P, Gupta D, Chaudhury S, Chaudhary M, Mittal A, Kumar S, Sahu SK. An Insight into the Development of Potential Antidiabetic Agents along with their Therapeutic Targets. Endocrine, Metabolic & Immune Disorders Drug Targets. 2023 May 22.
  51. Hammouda O, Chtourou H, Chaouachi A, Chahed H, Ferchichi S, Kallel C, Chamari K, Souissi N. Effect of short-term maximal exercise on biochemical markers of muscle damage, total antioxidant status, and homocysteine levels in football players. Asian journal of sports medicine. 2012 Dec;3(4):239.
  52. Sun X, Li W, Deng Y, Dong B, Sun Y, Xue Y, Wang Y. Hepatic conditional knockout of ATF6 exacerbates liver metabolic damage by repressing autophage through MTOR pathway. Biochemical and biophysical research communications. 2018 Oct 20;505(1):45-50.
  53. Norrbom JM, Ydfors M, Lovric A, Perry CG, Rundqvist H, Rullman E. A HIF-1 signature dominates the attenuation in the human skeletal muscle transcriptional response to high-intensity interval training. Journal of Applied Physiology. 2022 Jun 1;132(6):1448-59.
  54. Afrasyabi S, Marandi SM, Kargarfard M. The effects of high intensity interval training on appetite management in individuals with type 2 diabetes: influenced by participants weight. Journal of Diabetes & Metabolic Disorders. 2019 Jun 1;18:107-17.
  55. Aoki A, Murata M, Asano T, Ikoma A, Sasaki M, Saito T, Otani T, Jinbo S, Ikeda N, Kawakami M, Ishikawa SE. Prompt increases in retinol-binding protein 4 and endothelial progenitor cells during acute exercise load in diabetic subjects. Endocrine journal. 2012;59(12):1085-91.
Journal of Applied Health Studies in Sport Physiology
Volume 11, Issue 1
March 2024
Pages 96-110

Files

History

  • Receive Date: 29 September 2023
  • Revise Date: 30 September 2023
  • Accept Date: 09 October 2023

Share

How to cite

Statistics