Journal of Sport and Exercise Physiology

Journal of Sport and Exercise Physiology

Investigating the mutual effects of autophagy and apoptosis in heart tissue of type 2 diabetic rats in interaction with aerobic exercise training and vitamin D3 injection

Document Type : Original Article

Authors
Hadi Golpasandi 1
Mohammad Rahman Rahimi 1
Slahadin Ahmadi 2
1 Department of Exercise Physiology, Faculty of Humanities and Social Sciences, University of Kurdistan, Sanandaj, Iran
2 Department of Physiology and Pharmacology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
10.48308/joeppa.2024.235803.1257
Abstract
Background and Purpose: The interplay between autophagy and apoptosis is crucial in understanding heart health, particularly in the context of type 2 diabetes. The aim of this study was to investigate how aerobic training and vitamin D3 supplementation modulate the cardiac tissue of diabetic rats and highlight potential therapeutic strategies to improve cardiac function in diabetic conditions. Therefore, in this study, the effects of aerobic training and vitamin D3 injection on autophagy and apoptosis of heart tissue of diabetic rats were investigated.
Materials and Methods: Forty male Wistar rats with a weight range of 200 - 240 grams were divided into two groups receiving a standard diet (8 rats) and a high-fat diet (32 rats) for 6 weeks. After 6 weeks, in order to induce type 2 diabetes, 35 mg/kg body weight of streptozotocin (STZ) was injected intraperitoneally. Rats receiving high-fat diet were randomly divided into 4 groups, diabetes control (DC), diabetes + aerobic training (DAT), diabetes + vitamin D3 injection (DVD) and diabetes + aerobic training + vitamin D3 injection (DVDAT). The rats in the aerobic training group underwent aerobic training with an intensity of 60% of the maximum running speed through a treadmill for eight weeks, 3 sessions/week in the aerobic training groups. The groups receiving vitamin D3 received a diluted solution of vitamin D3 with sesame oil at a dose of 10000 IU/kg weekly. After the completion of aerobic training interventions and vitamin D3 injection and anesthetizing the mice, the heart tissue was extracted and the protein levels of Beclin -1, Bax and Bcl -2 in the left ventricle of the heart tissue were measured by western blot technique. The data were analyzed using one-way analysis of variance (ANOVA).
Results: Data analysis showed that type 2 diabetes increased the levels of Beclin-1, Bax and decreased Bcl-2 (P<0.001). Aerobic training, vitamin D3 and their interaction both decreased Beclin-1, Bax and increased Bcl -2, and that these changes were higher in the DVDAT group (P<0.001). The results also showed that fasting glucose levels and insulin resistance index decreased significantly in DAT, DVD and DVDAT groups (P<0.001), and this decrease was more in DVDAT group (P<0.001).
Conclusion: In general, it could be concluded that type 2 diabetes causes disturbances in cellular and metabolic homeostasis, including insulin resistance, through increased autophagy and apoptosis in heart tissue, which can be reversed through aerobic training and vitamin D3, and improve glucose metabolism and insulin resistance.
Keywords
Aerobic Exercise Training
Excessive Autophagy
Apoptosis
Bax
Beclin-1 and Diabetic Cardiomyopathy
Subjects

  1.  

    1. You S, Zheng J, Chen Y, Huang H. Research progress on the mechanism of beta-cell apoptosis in type 2 diabetes mellitus. Frontiers in Endocrinology. 2022 Aug 18;13:976465.
    2. Packer M. Autophagy-dependent and-independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs. Cardiovascular Diabetology. 2020;19(1):62.
    3. Golpasandi, Abdullahpour S, Golpasandi H. High-intensity interval training combined with saffron supplementation modulates stress-inflammatory markers in obese women with type 2 diabetes Research in Exercise Nutrition 2022, May 22; 1(1): 55-61 https://www.researchinexercisenutrition.com/article_62277.html?lang=en.
    4. Dewanjee S, Vallamkondu J, Kalra RS, John A, Reddy PH, Kandimalla R. Autophagy in the diabetic heart: a potential pharmacotherapeutic target in diabetic cardiomyopathy. Ageing research reviews. 2021;68:101338.
    5. Wang L-h, Wang Y-y, Liu L, Gong Q. From diabetes to diabetic complications: Role of autophagy. Current Medical Science. 2023;43(3):434-44.
    6. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circulation research. 2007;100(6):914-22.
    7. Das S, Shukla N, Singh SS, Kushwaha S, Shrivastava R. Mechanism of interaction between autophagy and apoptosis in cancer. Apoptosis. 2021:1-22.
    8. Faraji H, Rahimi MR, Taeimouri S. The Effect of Salvia Officinalis Extract on P53 and Creatine Kinase Levels in Downhill Running: A Crossover Randomized, Double-Blind, and Placebo-Controlled Study. Research in Exercise Nutrition. 2022;1(1):23-9.
    9. Gordy C, He Y-W. The crosstalk between autophagy and apoptosis: where does this lead? Protein & cell. 2012;3:17-27.
    10. Yao Q, Ke Z-q, Guo S, Yang X-s, Zhang F-x, Liu X-f, et al. Curcumin protects against diabetic cardiomyopathy by promoting autophagy and alleviating apoptosis. Journal of molecular and cellular cardiology. 2018;124:26-34.
    11. Yang J, Yao S. JNK-Bcl-2/Bcl-xL-Bax/Bak pathway mediates the crosstalk between matrine-induced autophagy and apoptosis via interplay with beclin 1. International journal of molecular sciences. 2015;16(10):25744-58.
    12. Maejima Y, Kyoi S, Zhai P, Liu T, Li H, Ivessa A, et al. Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nature medicine. 2013;19(11):1478-88.
    13. Kessel DH, Price M, Reiners J, John J. ATG7 deficiency suppresses apoptosis and cell death induced by lysosomal photodamage. Autophagy. 2012;8(9):1333-41.
    14. Dethlefsen MM, Halling JF, Møller HD, Plomgaard P, Regenberg B, Ringholm S, Pilegaard H. Regulation of apoptosis and autophagy in mouse and human skeletal muscle with aging and lifelong exercise training. Experimental Gerontology. 2018;111:141-53.
    15. Andreotti DZ, Silva JdN, Matumoto AM, Orellana AM, De Mello PS, Kawamoto EM. Effects of physical exercise on autophagy and apoptosis in aged brain: Human and animal studies. Frontiers in Nutrition. 2020;7:94.
    16. Wang L, Wang J, Cretoiu D, Li G, Xiao J. Exercise-mediated regulation of autophagy in the cardiovascular system. Journal of Sport and Health Science. 2020;9(3):203-10.
    17. Golpasandi H, Rahimi MR, Ahmadi S, Łubkowska B, Cięszczyk P. Effects of Vitamin D3 Supplementation and Aerobic Training on Autophagy Signaling Proteins in a Rat Model Type 2 Diabetes Induced by High-Fat Diet and Streptozotocin. Nutrients. 2023;15(18):4024.
    18. Azali Alamdari K, SatarZadeh R. Impact of Aerobic Training and Vitamin D Supplementation on Hunger Rate and Serum Ghrelin and Insulin in Middle Agead Females with Metablic Syndrome. Research in Exercise Nutrition. 2022;1(1):13-1. Doi: https://www.researchinexercisenutrition.com/article_62074.html?lang=en.
    19. Chen X, Arias Z, Omori K, Yamamoto T, Shinoda-Ito Y, Takashiba S. Autophagy as a potential mechanism underlying the biological effect of 1, 25-Dihydroxyvitamin D3 on periodontitis: a narrative review. BMC Oral Health. 2023;23(1):90.
    20. Ali TM, Abo-Salem OM, El Esawy BH, El Askary AJTAjotms. The potential protective effects of diosmin on streptozotocin-induced diabetic cardiomyopathy in rats. 2020;359(1):32-41.
    21. Kanter M, Aksu F, Takir M, Kostek O, Kanter B, Oymagil AJE, et al. Effects of low intensity exercise against apoptosis and oxidative stress in Streptozotocin-induced diabetic rat heart. 2017;125(09):583-91.
    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;47(6):1278-83.
    23. Machado MV, Martins RL, Borges J, Antunes BR, Estato V, Vieira AB, Tibirica E. Exercise training reverses structural microvascular rarefaction and improves endothelium-dependent microvascular reactivity in rats with diabetes. Metabolic syndrome and related disorders. 2016;14(6):298-304.
    24. Mehdipoor M, Damirchi A, Razavi Tousi SMT, Babaei P. Concurrent vitamin D supplementation and exercise training improve cardiac fibrosis via TGF-β/Smad signaling in myocardial infarction model of rats. Journal of physiology and biochemistry. 2021;77:75-84.
    25. Antunes LC, Elkfury JL, Jornada MN, Foletto KC, Bertoluci MC. Validation of HOMA-IR in a model of insulin-resistance induced by a high-fat diet in Wistar rats. Archives of endocrinology and metabolism. 2016;60:138-42.
    26. Golpasandi H, Rahimi M, Ahmadi S. Combined Effects of Vitamin D3 Supplementation and Aerobic Training on Cardiac Cathepsin D and Insulin Resistance in Diabetic Rats Induced by High-fat Diet and Streptozotocin. Iranian Journal of Endocrinology and Metabolism. 2023;24(6):362-72.
    27. Madonna R, Moscato S, Cufaro MC, Pieragostino D, Mattii L, Del Boccio P, et al. Empagliflozin inhibits excessive autophagy through the AMPK/GSK3β signalling pathway in diabetic cardiomyopathy. Cardiovascular Research. 2023;119(5):1175-89.
    28. Zhang K. “NO” to autophagy: fat does the trick for diabetes. Diabetes. 2018;67(2):180.
    29. Sehrawat A, Mishra J, Mastana SS, Navik U, Bhatti GK, Reddy PH, Bhatti JS. Dysregulated autophagy: A key player in the pathophysiology of type 2 diabetes and its complications. Biochimica et Biophysica Acta (BBA)-molecular basis of Disease. 2023;1869(4):166666.
    30. Kuramoto, K., Kim, Y.J., Hong, J.H. and He, C., 2021. The autophagy protein Becn1 improves insulin sensitivity by promoting adiponectin secretion via exocyst binding. Cell reports, 35(8).
    31. Luo S, Rubinsztein DC. BCL2L11/BIM: a novel molecular link between autophagy and apoptosis. Autophagy. 2013;9(1):104-5.
    32. Obeng E. Apoptosis (programmed cell death) and its signals-A review. Brazilian Journal of Biology. 2020;81:1133-43.
    33. Gao L, Liu F, Liu R. The mechanism of aerobic exercise regulating the PI3K/Akt-mTOR signaling pathway intervenes in hippocampal neuronal apoptosis in vascular dementia rats. International Journal of Environmental Research and Public Health. 2023;20(3):1893.
    34. Zanganeh F, Farzanegi P, Asgharpour H. Effect of Exercise Training and Atorvastatin Supplementation on Beclin1, LC3-I and LC3-П Expression in Old Diabetic Rats. Medical Laboratory Journal. 2022 Jan 1;16(1).
    35. Rocha-Rodrigues S, Gonçalves IO, Beleza J, Ascensão A, Magalhães J. Effects of endurance training on autophagy and apoptotic signaling in visceral adipose tissue of prolonged high fat diet-fed rats. European journal of nutrition. 2018;57:2237-47.
    36. Liu W, Wang Z, Xia Y, Kuang H, Liu S, Li L, et al. The balance of apoptosis and autophagy via regulation of the AMPK signal pathway in aging rat striatum during regular aerobic exercise. Experimental Gerontology. 2019;124:110647.
    37. Jafari A, Zarghami Khameneh A, Nikookheslat S, Karimi P, Pashaei Z. Effects of Two Months of High Intensity Interval Training and Caffeine Supplementation on the Expression of Beclin-1 and Bcl-2 Proteins in the Myocardium of Type 2 Male Diabetic Rats. Journal of Applied Health Studies in Sport Physiology. 2021;8(2):83-91.
    38. Xu H-D, Qin Z-H. Beclin 1, Bcl-2 and autophagy. Autophagy: Biology and Diseases: Basic Science. 2019:109-26.
    39. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005;122(6):927-39.
    40. Huang D, Guo Y, Li X, Pan M, Liu J, Zhang W, Mai K. Vitamin D 3/VDR inhibits inflammation through NF-κB pathway accompanied by resisting apoptosis and inducing autophagy in abalone Haliotis discus hannai. Cell Biology and Toxicology. 2021:1-22.
    41. Turkmen K. Inflammation, oxidative stress, apoptosis, and autophagy in diabetes mellitus and diabetic kidney disease: the Four Horsemen of the Apocalypse. International urology and nephrology. 2017;49:837-44.
    42. Yang J, Zhou R, Ma Z. Autophagy and energy metabolism. Autophagy: Biology and Diseases: Basic Science. 2019:329-57.

  • Receive Date 23 May 2024
  • Revise Date 29 June 2024
  • Accept Date 30 June 2024
  • First Publish Date 30 June 2024
  • Publish Date 21 June 2024