Document Type : original article


1 Associate Professor, Department of Sports Physiology, Faculty of Physical Education and Sport Sciences, University of Tabriz, Tabriz, Iran

2 Tabriz University

3 PhD Student of the Department of Sports Physiology, Faculty of Physical Education and Sport Sciences, University of Tabriz, Tabriz, Iran


Background and Purpose: The mechanistic target of rapamycin (mTOR) protein complex increases in response to resistance training with a histological approach and decreases in aerobic training with a metabolic approach. These changes can be discussed in the conditions of type 2 diabetes (T2DM) and with exercise. Therefore, taking into account exercises such as high-intensity interval training (HIIT) with aerobic and anaerobic characteristics and on the other hand T2DM intervention can depict the possible interaction of mTOR with glycemic and histopathological indicators of the cardiac. So, the present study was conducted to determine the effect of eight weeks of HIIT on p-mTOR, T-mTOR and fibrosis of cardiac tissue and insulin resistance on diabetic rats through STZ injection.
Material and Methods: Twenty male adult white Wistar rats were divided into four groups (N=5): healthy control, diabetic control, healthy workout and diabetic workout. The HIIT protocol was carried out five sessions a week for eight weeks on a treadmill. One-way analysis of variance was used for statistical analysis at a significance level of P < 0.05.
Results: The results showed that eight weeks of HIIT did not lead to significant changes in the amount of p-mTOR and T-mTOR in the cardiac tissue of rats with T2DM (P > 0.05); However, it caused a significant decrease in insulin resistance (31.2% compared to the diabetic control group) and cardiac tissue fibrosis (51.6% compared to the diabetic control group) in rats with T2DM (P < 0.05).
Conclusion: According to the results, it seems that eight weeks of HIIT is enough to observe the increase in amount of cardiac tissue mTOR in healthy rats, but it is insufficient in rats with T2DM. Also, it is possible that the reduction of cardiac tissue fibrosis in rats with T2DM, at least during eight weeks of HITT, is independent of cardiac tissue mTOR.


Main Subjects

  1. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. Elsevier; 2017;168(6):960–76.
  2. Kido K, Sase K, Yokokawa T, Fujita S. enhanced skeletal muscle insulin sensitivity after acute resistance-type exercise is upregulated by rapamycin-sensitive mtoR complex 1 inhibition. Sci Rep. Nature Publishing Group; 2020;10(1):1–12.
  3. Zhang Y, Huang B, Wang H-Y, Chang A, Zheng XFS. Emerging role of microRNAs in mTOR signaling. Cell Mol Life Sci. Springer; 2017;74(14):2613–25.
  4. Ye Y, Liu H, Zhang F, Hu F. mTOR signaling in Brown and Beige adipocytes: implications for thermogenesis and obesity. Nutr Metab (Lond). BioMed Central; 2019;16(1):1–14.
  5. Chong ZZ, Maiese K. Mammalian target of rapamycin signaling in diabetic cardiovascular disease. Cardiovasc Diabetol. Springer; 2012;11(1):1–8.
  6. Singh VP, Le B, Khode R, Baker KM, Kumar R. Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis. Diabetes. Am Diabetes Assoc; 2008;57(12):3297–306.
  7. Salem MM, Abdulazim DO. Recent Advances in Management of Diabetic Nephropathy. J Clin Exp Nephrol. 2017;2(2):35.
  8. Nikookheslat Dabbagh S, Novin N, Karimi P. Effect of Six Week High Intensity Interval Training (HIIT) with Chia Seed Supplementation on VEGF and Cardiac Fibrosis in Male Wistar Diabetic [Theses]. 2018;169. (In Persian).
  9. Atabakhshian R, Raygan F, Kazerouni F. Galectin-3 in fibrosis and heart failure. Clin Excell. Clinical Excellence; 2014;2(2):36–49.
  10. Torre-Villalvazo I, Alemán-Escondrillas G, Valle-Ríos R, Noriega LG. Protein intake and amino acid supplementation regulate exercise recovery and performance through the modulation of mTOR, AMPK, FGF21, and immunity. Nutr Res. Elsevier; 2019;72:1–17.
  11. Nemati J, Samadi M, Hadidi V, Macintash B. Effect of Resistance Training on Mtor and P70s6k Signaling Pathway in Skeletal Muscle of Rats. Jornal of Sport and Exercise Physiology; 2015;8(1):1149–56. (In Persian).
  12. Torma F, Gombos Z, Jokai M, Takeda M, Mimura T, Radak Z. High intensity interval training and molecular adaptive response of skeletal muscle. Sport Med Heal Sci. Elsevier; 2019;1(1):24–32.
  13. Agostini D, Natalucci V, Baldelli G, De Santi M, Donati Zeppa S, Vallorani L, et al. New insights into the role of exercise in inhibiting mTOR signaling in triple-negative breast cancer. Oxid Med Cell Longev. Hindawi; 2018;2018:1–19.
  14. Batrakoulis A, Fatouros IG, Chatzinikolaou A, Draganidis D, Georgakouli K, Papanikolaou K, et al. Dose-response effects of high-intensity interval neuromuscular exercise training on weight loss, performance, health and quality of life in inactive obese adults: Study rationale, design and methods of the DoIT trial. Contemp Clin trials Commun. Elsevier; 2019;15:100386.
  15. Sasidharan SR, Joseph JA, Anandakumar S, Venkatesan V, Ariyattu Madhavan CN, Agarwal A. An experimental approach for selecting appropriate rodent diets for research studies on metabolic disorders. Biomed Res Int. Hindawi; 2013;2013(752870):9.
  16. Brown MB, Neves E, Long G, Graber J, Gladish B, Wiseman A, et al. High-intensity interval training, but not continuous training, reverses right ventricular hypertrophy and dysfunction in a rat model of pulmonary hypertension. Am J Physiol Integr Comp Physiol. American Physiological Society Bethesda, MD; 2017;312(2):R197–210.
  17. Bedford TG, Tipton CM, Wilson NC, Oppliger RA, Gisolfi C V. Maximum oxygen consumption of rats and its changes with various experimental procedures. J Appl Physiol. 1979;47(6):1278–83.
  18. PITHON-CURI TNIAC. Aprogram Of Moderate Physical Training For Wistar Rats Based On Maximal Oxygen Consumption. J strength Cond Res. 2007;21(3):38–43.
  19. Liao J, Li Y, Zeng F, Wu Y. Regulation of mTOR pathway in exercise-induced cardiac hypertrophy. Int J Sports Med. © Georg Thieme Verlag KG; 2015;36(05):343–50.
  20. Jokar M, Zarei F, Moghadam MS, Palavani HA. Effect of 8-Week Endurance Training on the Content of Mtor and SREBP1 Proteins in Subcutaneous Fat Tissue in Obese Type 2 Diabetic Male Sprague-Dawley Rats. J Shahid Sadoughi Univ Med Sci. 2020;28(6):2755–65. (In Persian).
  21. Jokar M, Sherafati Moghadam M, Daryanoosh F. The effect of a period of high-intensity interval training on the content of AMPK and PGC-1α proteins in the heart muscle tissue of rats with type 2 diabetes. Daneshvar Med. Shahed University; 2021;29(1):23–34.
  22. Dela F, Ploug T, Handberg A, Petersen LN, Larsen JJ, Mikines KJ, et al. Physical training increases muscle GLUT4 protein and mRNA in patients with NIDDM. Diabetes. Am Diabetes Assoc; 1994;43(7):862–5.
  23. Launay T, Momken I, Carreira S, Mougenot N, Zhou X-L, De Koning L, et al. Acceleration-based training: A new mode of training in senescent rats improving performance and left ventricular and muscle functions. Exp Gerontol. Elsevier; 2017;95:71–6.
  24. Shadmehri S, Sharafati Moghadam M. The effect of four weeks high-intensity interval training (HIIT) on the content of AKT1, mTOR, P70S6K1, 4EBP1 proteins in the Left ventricular muscle tissue of the heart obese rats with type 2 diabetic. Jornal of Sport and Exercise Physiology; 2021;14(1):85–94. (In Persian).
  25. Peeri M, Azarbayjani M-A. The Effect of Detraining High Intensity Interval Training on the Expression of AKT1 and mTORc1 Genes in the Left Ventricle of Diabetic Rats. Iran J Diabetes Obes. 2020;12(1):37–46. (In Persian).
  26. Mirsepasi M, Baneifar AA, Azarbayjani MA, Arshadi S. The Effects of High Intensity Interval Training on Gene Expression of AKT1 and mTORc1 in the Left Ventricle of Type 2 Diabetic Rats: An Experimental Study. J Rafsanjan Univ Med Sci. Journal of Rafsanjan University of Medical Sciences; 2019;17(12):1119–30. (In Persian).
  27. Dreyer HC, Fujita S, Cadenas JG, Chinkes DL, Volpi E, Rasmussen BB. Resistance exercise increases AMPK activity and reduces 4E‐BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol. Wiley Online Library; 2006;576(2):613–24.
  28. Medeiros C, Frederico MJ, da Luz G, Pauli JR, Silva ASR, Pinho RA, et al. Exercise training reduces insulin resistance and upregulates the mTOR/p70S6k pathway in cardiac muscle of diet‐induced obesity rats. J Cell Physiol. Wiley Online Library; 2011;226(3):666–74.
  29. Sanches-Silva A, Testai L, Nabavi SF, Battino M, Devi KP, Tejada S, et al. Therapeutic potential of polyphenols in cardiovascular diseases: Regulation of mTOR signaling pathway. Pharmacol Res. Elsevier; 2020;152:104626.
  30. Chengji W, Xianjin F. Exercise protects against diabetic cardiomyopathy by the inhibition of the endoplasmic reticulum stress pathway in rats. J Cell Physiol. Wiley Online Library; 2019;234(2):1682–8.
  31. Novoa U, Arauna D, Moran M, Nuñez M, Zagmutt S, Saldivia S, et al. High-intensity exercise reduces cardiac fibrosis and hypertrophy but does not restore the nitroso-redox imbalance in diabetic cardiomyopathy. Oxid Med Cell Longev. Hindawi; 2017;2017(7921363):11.
  32. Luneva EB, Vasileva AA, Karelkina E V, Boyarinova MA, Mikhaylov EN, Ryzhkov A V, et al. Simple Predictors for Cardiac Fibrosis in Patients with Type 2 Diabetes Mellitus: The Role of Circulating Biomarkers and Pulse Wave Velocity. J Clin Med. MDPI; 2022;11(10):2843.
  33. Soori R, Amini AA, Choobineh S, Eskandari A, Behjat A, Ghram A, et al. Exercise attenuates myocardial fibrosis and increases angiogenesis-related molecules in the myocardium of aged rats. Arch Physiol Biochem. Taylor & Francis; 2022;128(1):1–6.
  34. Salvador Jr DB, Gamba MR, Gonzalez-Jaramillo N, Gonzalez-Jaramillo V, Raguindin PFN, Minder B, et al. Diabetes and myocardial fibrosis: a systematic review and meta-analysis. Cardiovasc Imaging. American College of Cardiology Foundation Washington DC; 2022;15(5):796–808.
  35. Shi X, Chen X, Qiu X, Luo W, Luo X, Liu H, et al. Effect of High-Intensity Interval Training, Moderate Continuous Training, or Guideline-Based Physical Activity on Peak Oxygen Uptake and Myocardial Fibrosis in Patients With Myocardial Infarction: Protocol for a Randomized Controlled Trial. Front Cardiovasc Med. Frontiers Media SA; 2022;9:860071.
  36. Verboven M, Cuypers A, Deluyker D, Lambrichts I, Eijnde BO, Hansen D, et al. High intensity training improves cardiac function in healthy rats. Sci Rep. Nature Publishing Group; 2019;9(1):1–8.
  37. Amri J, Parastesh M, Sadegh M, Latifi SA, Alaee M. High-intensity interval training improved fasting blood glucose and lipid profiles in type 2 diabetic rats more than endurance training; possible involvement of irisin and betatrophin. Physiol Int. Akadémiai Kiadó Budapest; 2019;106(3):213–24.
  38. Mateo-Gallego R, Madinaveitia-Nisarre L, Giné-Gonzalez J, Bea AM, Guerra-Torrecilla L, Baila-Rueda L, et al. The effects of high-intensity interval training on glucose metabolism, cardiorespiratory fitness and weight control in subjects with diabetes: systematic review a meta-analysis. Diabetes Res Clin Pract. Elsevier; 2022;16(11):942–61.