High-intensity interval training reduces Tau and beta-amyloid accumulation by improving lactate-dependent mitophagy in rats with type 2 diabetes

Document Type : Original Article

Authors

1 Department of Sports Physiology, Faculty of Physical Education and Sports Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran

2 i+HeALTH Strategic Research Group, Department of Health Sciences, Miguel de Cervantes European University (UEMC), 47012 Valladolid, Spain

Abstract

Objective(s): This study aimed to investigate the effect of 8-week high-intensity interval training (HIIT) on lactate-induced mitophagy in the hippocampus of rats with type 2 diabetes.
Materials and Methods: 28 Wistar male rats were divided into four groups randomly: (i) control (Co), (ii) exercise (EX), (iii) type 2 diabetes (T2D), and (iv) type 2 diabetes + exercise (T2D + Ex). The rats in the T2D and T2D + Ex groups were fed a high-fat diet for two months, then a single dose of STZ (35 mg/kg) was injected to induce diabetes. The EX and T2D + Ex groups performed 4–10 intervals of treadmill running at 80–100% of Vmax. Serum and hippocampal levels of lactate, as well as hippocampal levels of monocarboxylate transporter2 (MCT2), sirtuin1 (SIRT1), forkhead box protein O (FOXO3), light chain 3 (LC3), PTEN-induced kinase 1 (PINK1), parkin, beta-amyloid (Aβ), hyperphosphorylated tau protein (TAU), Malondialdehyde (MDA), and antioxidant enzymes were measured. One-way ANOVA and Tukey post-hoc tests were used to analyze the data. 
Results: Serum and hippocampal levels of lactate as well as hippocampal levels of MCT2, SIRT1, FOXO3, LC3, PINK1, Parkin, and antioxidant enzymes were higher while hippocampal levels of Aβ, TAU, and MDA were lower in T2D+EX compared to T2D group (P-value<0.05)
Conclusion: HIIT could improve mitophagy through Lactate-SIRT1-FOXO3-PINK1/Parkin signaling in the hippocampus of rats with T2D reducing the accumulation of Tau and Aβ, which may reduce the risk of memory impairments.    

Keywords

Main Subjects


1. Dodson M, Darley-Usmar V, Zhang J. Cellular metabolic and autophagic pathways: traffic control by redox signaling. Biol Med 2013; 63:207-221.
2. Newmeyer DD, Ferguson-Miller S. Mitochondria: releasing power for life and unleashing the machineries of death. Cell 2003; 112:481-490.
3. Khoramipour K, Gaeini AA, Shirzad E, Gilany K, Chamari K, Sandbakk Ø. Using metabolomics to differentiate player positions in elite male basketball games: a pilot study. Front Mol Biosci 2021; 8:639786: 1-12.
4. Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J 2012; 441:523-540.
5. Burtscher J, Soltany A, Visavadiya NP, Burtscher M, Millet GP, Khoramipour K, et al. Mitochondrial stress and mitokines in aging. Aging Cell 2023; 22:e13770:1-12.
6. Cecconi F, Levine B. The role of autophagy in mammalian development: cell makeover rather than cell death. Dev Cell 2008; 15:344-357.
7. Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, et al. ABAD directly links Aß to mitochondrial toxicity in Alzheimer’s disease. Science 2004; 304:448-452.
8. Khoramipour K, Hekmatikar AA, Sotvan H. An overview of Fatmax and MFO in exercise. Razi J Med Sci 2020; 27:49-59.
9. Du H, Guo L, Fang F, Chen D, A Sosunov A, M McKhann G, et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 2008; 14:1097-1105.
10. Dumont M, Stack C, Elipenahli C, Jainuddin S, Gerges M, Starkova NN, et al. Behavioral deficit, oxidative stress, and mitochondrial dysfunction precede tau pathology in P301S transgenic mice. FASEB J 2011; 25: 4063-4077.
11. Akter M, Ma H, Hasan M, Karim A, Zhu X, Zhang L, et al. Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense. Front mol neurosci 2023; 16:1117146: 1-15.
12. Hu J, Cai M, Shang Q, Li Z, Feng Y, Liu B, et al. Elevated lactate by high-intensity interval training regulates the hippocampal BDNF expression and the mitochondrial quality control system. Front Physiol 2021; 12:629914:1-14.
13. Marunaka Y. Roles of interstitial fluid pH in diabetes mellitus: Glycolysis and mitochondrial function. World J Diabetes 2015; 6: 125-135.
14. Shima T, Kawabata-Iwakawa R, Onishi H, Jesmin S, Yoshikawa T. Light-intensity exercise improves memory dysfunction with the restoration of hippocampal MCT2 and miRNAs in type 2 diabetic mice. Metab Brain Dis 2023; 38:245-254.
15. El Hayek L, Khalifeh M, Zibara V, Abi Assaad R, Emmanuel N, Karnib N, et al. Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF). J Neurosci 2019; 39:2369-2382.
16. Komilova NR, Angelova PR, Berezhnov AV, Stelmashchuk OA, Mirkhodjaev UZ, Houlden H, et al. Metabolically induced intracellular pH changes activate mitophagy, autophagy, and cell protection in familial forms of Parkinson’s disease. FEBS J 2022; 289:699-711.
17. Fritzen AM, Frøsig C, Jeppesen J, Jensen TE, Lundsgaard A-M, Serup AK, et al. Role of AMPK in regulation of LC3 lipidation as a marker of autophagy in skeletal muscle. Cell Signal 2016; 28:663-674.
18. Olmos Y, Sánchez-Gómez FJ, Wild B, García-Quintans N, Cabezudo S, Lamas S, et al. SirT1 regulation of antioxidant genes is dependent on the formation of a FoxO3a/PGC-1α complex. Antioxid Redox Signal 2013; 19:1507-1521.
19. Cao Y, Yan Z, Zhou T, Wang G. SIRT1 regulates cognitive performance and ability of learning and memory in diabetic and nondiabetic models. J Diabetes Res 2017; 14:1-22.
20. Das S, Mitrovsky G, Vasanthi HR, Das DK. Antiaging properties of a grape-derived antioxidant are regulated by mitochondrial balance of fusion and fission leading to mitophagy triggered by a signaling network of Sirt1-Sirt3-Foxo3-PINK1-PARKIN. Oxid Med Cell Longev 2014; 2014:345105:1-23. 
21. Hariharan N, Maejima Y, Nakae J, Paik J, DePinho RA, Sadoshima J. Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ Res 2010; 107:1470-1482.
22. Xin Z, Ma Z, Jiang S, Wang D, Fan C, Di S, et al. FOXOs in the impaired heart: New therapeutic targets for cardiac diseases. Biochimica et Biophysica Acta (BBA)- Biochim Biophys Acta 2017; 1863:486-498.
23. Bai H, Yang F, Jiang W, Hu A, Chang H, Zhang Y, et al. Molybdenum and cadmium co-induce mitophagy and mitochondrial dysfunction via ROS-mediated PINK1/Parkin pathway in Hepa1-6 cells. Ecotoxicol Environ Saf 2021; 224:112618:1-10.
24. Shefa U, Jeong NY, Song IO, Chung H-J, Kim D, Jung J, et al. Mitophagy links oxidative stress conditions and neurodegenerative diseases. Neural Regen Res 2019; 14: 749-756.
25. Li B, Liang F, Ding X, Yan Q, Zhao Y, Zhang X, et al. Interval and continuous exercise overcome memory deficits related to β-Amyloid accumulation through modulating mitochondrial dynamics. Behav Brain Res 2019; 376:112171:1-10.
26. Melo CS, Rocha-Vieira E, Freitas DA, Soares BA, Rocha-Gomes A, Riul TR, et al. A single session of high-intensity interval exercise increases antioxidants defenses in the hippocampus of Wistar rats. Physiol Behav 2019; 211:112675:1-9.
27. Bragazzi NL, Khoramipour K, Chaouachi A, Chamari K. Toward sportomics: Shifting from sport genomics to sport postgenomics and metabolomics specialties. Promises, challenges, and future perspectives. Int J Sports Physiol Perform 2020; 15:1201-1202.
28. Lee MR, Kim JE, Choi JY, Park JJ, Kim HR, Song BR, et al. Anti‑obesity effect in high‑fat‑diet‑induced obese C57BL/6 mice: Study of a novel extract from mulberry (Morus alba) leaves fermented with Cordyceps militaris. Exp Ther Med 2019; 17:2185-2193.
29. Shimizu Y, Son C, Aotani D, Nomura H, Hikida T, Hosoda K, et al. Role of leptin in conditioned place preference to high-fat diet in leptin-deficient ob/ob mice. Neurosci Lett 2017; 640:60-63.
30. Eliza J, Daisy P, Ignacimuthu S, Duraipandiyan V. Antidiabetic and antilipidemic effect of eremanthin from Costus speciosus (Koen.) Sm., in STZ-induced diabetic rats. Chem Biol Interact 2009; 182:67-72.
31. Rami M, Azimpour M, Khoramipour K. The effect of 8 weeks of High Intensity Interval Training on the Levels of Wnt and NF-κB proteins in the heart tissue of male Wistar rats with type 2 diabetes. J Sport Exercise Physiol 2022; 15:19-30.
32. Speisman RB, Kumar A, Rani A, Foster TC, Ormerod BK. Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats. Brain Behav Immun 2013; 28:25-43.
33. Rami M, Rahdar S, Azimpour M, Khoramipour K. The effect of high intensity interval training on FOXO3, PI3K and AKT proteins content in heart muscle of type two diabetic rats. JPSBS 2023; 11:8-21.
34. Ramezani N, Dezhan M, Khalili SS, Shakeri N, Khoramipour K. Effect of high-intensity interval training on omentin-1 serum levels, gene expression, and insulin resistance in type 2 diabetic rats. Med Lab J 2023; 17:20-22.
35. Bejeshk MA, Rajizadeh MA, Najafipour H, Dehghan P. High-intensity interval training ameliorate diabetes-induced disturbances in Alzheimer’s-related factors in the hippocampus through adiponectin signaling.  2022; 17:1-22.
36. Orumiyehei A, Khoramipour K, Rezaei MH, Madadizadeh E, Meymandi MS, Mohammadi F, et al. High-intensity interval training-induced hippocampal molecular changes associated with improvement in anxiety-like behavior but not cognitive function in rats with type 2 diabetes. Brain Sci 2022; 12:1280:1-15.
37. Ebrahimnezhad N, Nayebifar S, Soltani Tajabadi Z, Khoramipour K. High-intensity interval training reduced oxidative stress and apoptosis in the hippocampus of male rats with type 2 diabetes: The role of the PGC1α-Keap1-Nrf2 signaling pathway. Iran J Basic Med Sci 2023; 26:273-282.
38. Rezaei MH, Madadizadeh E, Aminaei M, Abbaspoor M, Schierbauer J, Moser O, et al. Leptin Signaling Could Mediate Hippocampal Decumulation of Beta-Amyloid and Tau Induced by High-Intensity Interval Training in Rats with Type 2 Diabetes. Cell Mol Neurobiol 2023:1-14.
39. Joukar S, Rajizadeh MA, Bejeshk MA, Alavi SS, Bagheri F, Rami M, et al. ATP releasing channels and the ameliorative effects of high intensity interval training on diabetic heart: a multifaceted analysis. Sci Rep 2024; 14:7113:1-12.
40. Saberi S, Askaripour M, Khaksari M, Rajizadeh MA, Bejeshk MA, Akhbari M, et al. Exercise training improves diabetic renal injury by reducing fetuin-A, oxidative stress and inflammation in type 2 diabetic rats. Heliyon 2024; 10: e27749:1-11.
41. Rajizadeh MA, Khoramipour K, Joukar S, Darvishzadeh-Mahani F, Iranpour M, Bejeshk MA, et al. Lung molecular and histological changes in type 2 diabetic rats and its improvement by high-intensity interval training. BMC Pulm Med 2024; 24:37.
42. Pirani H, Soltany A, Hossein Rezaei M, Khodabakhshi Fard A, Nikooie R, Khoramipoor K, et al. Lactate-induced autophagy activation: unraveling the therapeutic impact of high-intensity interval training on insulin resistance in type 2 diabetic rats. Sci Rep 2024; 14:1108:1-10.
43. Khoramipour K, Rezaei MH, Madadizadeh E, Hosseini MS, Soltani Z, Schierbauer J, et al. High intensity interval training can ameliorate hypothalamic appetite regulation in male rats with type 2 diabetes: the role of Leptin. Cell Mol Neurobiol 2023; 43:4295-4307.
44. Rezaei MH, Madadizadeh E, Aminaei M, Abbaspoor M, Schierbauer J, Moser O, et al. Leptin signaling could mediate hippocampal decumulation of beta-amyloid and tau induced by high-intensity interval training in rats with type 2 diabetes. Cell Mol Neurobiol 2023; 43:3465-3478.
45. Rajizadeh MA, Moslemizadeh A, Hosseini MS, Rafiei F, Soltani Z, Khoramipour K. Adiponectin receptor 1 could explain the sex differences in molecular basis of cognitive improvements induced by exercise training in type 2 diabetic rats. Sci Rep 2023; 13:16267:1-9.
46. Rami M, Rahdar S, Azimpour M, Khoramipour K. The effect of high intensity interval training (HIIT) on PI3K-AKT-FOXO3 protein content in heart muscle of type 2 diabetic model rats. JPSBS 2023; 11:8-21.
47. Khajehlandi M, Bolboli L, Siahkuhian M, Rami M, Tabandeh M, Khoramipour K, et al. Endurance training regulates expression of some angiogenesis-related genes in cardiac tissue of experimentally induced diabetic rats. Biomolecules 2021; 11:498:1-11.
48. Khoramipour K, Katanchi A, Hajirasouli M, Behbudi L, Basereh A, Dehghan P, et al. Combined training in patient with aids: improved quality of life and preserved BDNF. Sport Sci Health 2022; 18:39-46.
49. Basereh A, Ebrahim K, Hovanloo F, Dehghan P, Khoramipour K. Effect of blood flow restriction deal during isometric exercise on growth hormone and testosterone active males. J Sport Physiol 2017; 9:51-68.
50. Rajizadeh MA, Hosseini MH, Bahrami M, Hosseini NS, Rostamabadi F, Bagheri F, et al. Comparison of preventive and therapeutic effects of continuous exercise on acute lung injury induced with methotrexate. Exp Physiol 2023; 108:1215-1227.
51. Rajizadeh MA, Hosseini MH, Bahrami M, Bahri F, Rostamabadi F, Bagheri F, et al. High-intensity intermittent training ameliorates methotrexate-induced acute lung injury. BMC Pulm Med 2024; 24:45:1-9.
52. Rahmaty S, Dehghan P, Khoramipour K, Saboory M. The effect of listening to brain waves’ relaxing and exciting music during intense endurance training on blood cortisol levels of adult men. AJSSM 2015; 3:77-81.
53. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol 2011; 12:9-14.
54. Marques-Aleixo I, Santos-Alves E, Balça M, Rizo-Roca D, Moreira P, Oliveira P, et al. Physical exercise improves brain cortex and cerebellum mitochondrial bioenergetics and alters apoptotic, dynamic and auto (mito) phagy markers. Neurosci 2015; 301:480-495.
55. Pierre K, Pellerin L. Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem 2005; 94:1-14.
56. Dienel GA, Hertz L. Glucose and lactate metabolism during brain activation. J Neurosci Res 2001; 66:824-838.
57. Jacob N, So I, Sharma B, Marzolini S, Tartaglia MC, Oh P, et al. Effects of High-Intensity Interval Training Protocols on Blood Lactate Levels and Cognition in Healthy Adults: Systematic Review and Meta-Regression. J Sports Med 2023; 53:977-991.
58. Park J, Kim J, Mikami T. Exercise-induced lactate release mediates mitochondrial biogenesis in the hippocampus of mice via monocarboxylate transporters. Front Physiol 2021; 12:736905:1-11.
59. Park J, Kim J, Mikami T. Exercise-induced lactate release mediates mitochondrial biogenesis in the hippocampus of mice via monocarboxylate transporters. Front Physiol 2021; 12:1486:1-14.
60. Jacob N, So I, Sharma B, Marzolini S, Tartaglia MC, Oh P, et al. Effects of High-Intensity Interval Training Protocols on Blood Lactate Levels and Cognition in Healthy Adults: Systematic Review and Meta-Regression. J Sports Med 2023:1-15.
61. Van Hall G, Stømstad M, Rasmussen P, Jans Ø, Zaar M, Gam C, et al. Blood lactate is an important energy source for the human brain. J Cereb Blood Flow Metab 2009; 29:1121-1129.
62. Zhang Y, Liao B, Hu S, Pan S-Y, Wang G-P, Wang Y-L, et al. High intensity interval training induces dysregulation of mitochondrial respiratory complex and mitophagy in the hippocampus of middle-aged mice. Behav Brain Res 2021; 412:113384:1-10.
63. Fujimaki S, Kuwabara T. Diabetes-induced dysfunction of mitochondria and stem cells in skeletal muscle and the nervous system. Int J Mol Sci 2017; 18:2147:1-15.
64. Yuan Y, Cruzat VF, Newsholme P, Cheng J, Chen Y, Lu Y. Regulation of SIRT1 in aging: roles in mitochondrial function and biogenesis. Mech Ageing Dev 2016; 155:10-21.
65. Askarian A, Kordi M, Choobineh S, Gaeini A. High Intensity Interval Training Is More Beneficial to Regulate Free Radicals and mtDNA Oxidative Damage in Aged Rats.  2022; 7:1-16.
66. Quinn PM, Moreira PI, Ambrósio AF, Alves CH. PINK1/PARKIN signalling in neurodegeneration and neuroinflammation. Acta Neuropathol Commun 2020; 8:1-20.
67. Chen CCW, Erlich AT, Hood DA. Role of Parkin and endurance training on mitochondrial turnover in skeletal muscle. Skelet Muscle 2018; 8:1-14.
68. Li H, Miao W, Ma J, Xv Z, Bo H, Li J, et al. Acute exercise-induced mitochondrial stress triggers an inflammatory response in the myocardium via NLRP3 inflammasome activation with mitophagy. Oxid Med Cell Longev 2016; 1987149:1-11.
69. Brandt N, Gunnarsson TP, Bangsbo J, Pilegaard H. Exercise and exercise training‐induced increase in autophagy markers in human skeletal muscle. Physiol Rep 2018; 6:e13651:1-10.
70. Völgyi K, Háden K, Kis V, Gulyássy P, Badics K, Györffy BA, et al. Mitochondrial proteome changes correlating with β-amyloid accumulation. Mol Neurobiol 2017; 54:2060-2078.
71. Naderi S, Habibi A, Kesmati M, Rezaie A, Ghanbarzadeh M. The Effects of Six Weeks High Intensity Interval Training on Amyloid Beta1-42 Peptide in Hippocampus of Rat Model of Alzheimer’s Disease Induced with STZ. J Clin Res Paramed Sci  2018; 1-5.
72. Liang J, Wang C, Zhang H, Huang J, Xie J, Chen N. Exercise-induced benefits for Alzheimer’s disease by stimulating mitophagy and improving mitochondrial function. Front aging neurosci 2021; 13:1-17.