Exercise training attenuates diabetes-induced cardiac injury through increasing miR-133a and improving pro-apoptosis/anti-apoptosis balance in ovariectomized rats

Document Type: Original Article


1 Neurophysiology research center, Hamadan University of Medical Sciences, Hamadan, Iran

2 Department of Histology & Embryology, Tabriz University of Medical Sciences, Tabriz, Iran

3 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

4 Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran

5 Department of Physiology, School of Medicine, Ilam University of Medical Science, Ilam, Iran


Objective(s): The useful and effective role of exercise program to prevent cardiac tissue apoptosis and fibrosis in ovariectomized type 2 diabetic (T2DM) rats (OVR.D) is well known. The current study aimed to investigate the simultaneous effects of T2DM and swimming plan on the expression of some apoptotic, anti-apoptotic biomarkers and glycogen changes in the cardiac muscle tissue of ovariectomized (OVR) rats.
Materials and Methods: Forty rats were randomly sorted into 4 equal categories; sham, OVR, OVR.D and diabetic ovariectomized with an 8 week of swimming plan (OVR.D.E). Lipid profile and miR-133, Bcl-2, Bax, caspase-3 and caspase-8 levels were evaluated in the cardiac tissue.
Results: Ovariectomy significantly (P-value<0.05) increased cholesterol, triglyceride, LDL, Bax, caspase-3, caspase-8 and decreased (P-value<0.05) HDL, miR-133, Bcl-2 in the cardiac tissue and a further reduction in the expression of miR-133, Bcl-2 and an enhancement in Bax, caspase-3 and caspase-8 in OVR.D rats was observed (P-value<0.01). However, exercise training significantly reversed all the measured parameters (P-value<0.05). Also, exercise training improved abnormal tissue structure, fragmentation and irregular form of glycogen granules in the OVR.D.E compared to OVR and OVR.D animals.
Conclusion: Exercise training could prevent the cardiac disturbance, enhance the expression of anti-apoptotic markers and decrease apoptotic biomarkers in the hearts of OVR.D animals. Therefore, based on the findings of this study suggested using the exercise’s beneficial effects for prevention of the cardiac cell death in OVR.D animals.


1. Stoney R, O’dea K, Herbert K, Dragicevic G, Giles G, Cumpston G, et al. Insulin resistance as a major determinant of increased coronary heart disease risk in postmenopausal women with Type 2 diabetes mellitus. Diabet Med 2001; 18: 476-482.
2. León LE, Rani S, Fernandez M, Larico M, Calligaris SD. Subclinical detection of diabetic cardiomyopathy with microRNAs: challenges and perspectives. J Diabetes Res 2016; 2016: 1-12.
3. Chae CU, Derby CA. The menopausal transition and cardiovascular risk. Obstet Gynecol Clin North Am 2011; 38: 477-488.
4. Sanches IC, Buzin M, Conti FF, da Silva Dias D, dos Santos CP, Sirvente R, et al. Combined aerobic and resistance exercise training attenuates cardiac dysfunctions in a model of diabetes and menopause. PloS One J 2018; 13: 1-15.
5. Saengsirisuwan V, Pongseeda S, Prasannarong M, Vichaiwong K, Toskulkao C. Modulation of insulin resistance in ovariectomized rats by endurance exercise training and estrogen replacement. Metabolism  2009; 58: 38-47.
6. Lew JKS, Pearson JT, Schwenke DO, Katare R. Exercise mediated protection of diabetic heart through modulation of microRNA mediated molecular pathways. Cardiovasc diabetol 2017; 16: 1-20.
7. Masi LN, Serdan TDA, Levada-Pires AC, Hatanaka E, dos Reis Silveira L, Cury-Boaventura MF, et al. Regulation of gene expression by exercise-related micrornas. Cell Physiol Biochem 2016; 39: 2381-2397.
8. Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996; 335: 453-461.
9. Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999; 100: 1134-1146.
10. Habibi P, Alihemmati A, Nasirzadeh M, Yousefi H, Habibi M, Ahmadiasl N. Involvement of microRNA-133 and-29 in cardiac disturbances in diabetic ovariectomized rats. Iran J Basic Med Sci 2016; 19:1177-1185.
11. He Y, Ding Y, Liang B, Lin J, Kim T-K, Yu H, et al. A systematic study of dysregulated microRNA in type 2 diabetes mellitus. Int J Mol Sci 2017; 18: 1-23.
12. Shantikumar S, Caporali A, Emanueli C. Role of microRNAs in diabetes and its cardiovascular complications. Cardiovasc Res 2012; 93: 583-593.
 13. Small EM, Frost RJ, Olson EN. MicroRNAs add a new dimension to cardiovascular disease. Circulation 2010; 121: 1022-1032.
14. Han Y, Chen Y-S, Liu Z, Bodyak N, Rigor D, Bisping E, et al. Overexpression of HAX-1 protects cardiac myocytes from apoptosis through caspase-9 inhibition. Circ Res 2006; 99: 415-423.
15. Xu C, Lu Y, Pan Z, Chu W, Luo X, Lin H, et al. The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis by targeting HSP60, HSP70 and caspase-9 in cardiomyocytes. J Cell Sci 2007; 120: 3045-3052.
16. Habibi P, Alihemmati A, NourAzar A, Yousefi H, Mortazavi S, Ahmadiasl N. Expression of the Mir-133 and Bcl-2 could be affected by swimming training in the heart of ovariectomized rats. Iran J Basic Med Sci 2016; 19: 381-387.
17. Ed G. Guide for the care and use of laboratory animals. National Research Council. 8th ed. Washington, DC, USA 2011.
18. Karimi A, Joukar S, Najafipour H, Masoumi-Ardakani Y, Shahouzehi B. Low-intensity endurance exercise plus nandrolone decanoate modulates cardiac adiponectin and its receptors. Auton Autacoid Pharmacol 2017; 37: 29-33.
19. Joukar S, Najafipour H, Dabiri S, Sheibani M, Sharokhi N. Cardioprotective effect of mumie (shilajit) on experimentally induced myocardial injury. Cardiovasc Toxicol 2014; 14: 214-221.
20. Duisters RF, Tijsen AJ, Schroen B, Leenders JJ, Lentink V, van der Made I, et al. miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ Res 2009; 104: 170–178.
21. Chen S, Puthanveetil P, Feng B, Matkovich SJ, Dorn GW, Chakrabarti S. Cardiac miR-133a overexpression prevents early cardiac fibrosis in diabetes. J Cell Mol Med 2014; 18: 415–421.
22. Rawal S, Manning P, Katare R. Cardiovascular microRNAs: as modulators and diagnostic biomarkers of diabetic heart disease. Cardiovasc Diabetol 2014; 13: 1-24.
23. Yildirim SS, Akman D, Catalucci D, Turan B. Relationship between downregulation of miRNAs and increase of oxidative stress in the development of diabetic cardiac dysfunction: junctin as a target protein of miR-1. Cell Biochem Biophys 2013; 67: 1397–1408.
24. Anbinder AL, Prado MdA, Spalding M, Balducci I, Carvalho YR, Rocha RFd. Estrogen deficiency and periodontal condition in rats: a radiographic and macroscopic study. Braz Dent J 2006; 17: 201-207.
25. Lizcano F, Guzmán G. Estrogen deficiency and the origin of obesity during menopause. Biomed Res Int  2014; 2014: 1-11.