The effects of combined resveratrol and high intensity interval training on the hippocampus in aged male rats: An investigation into some signaling pathways related to mitochondria

Document Type : Original Article

Authors

1 Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

2 Shiraz University International Division, Shiraz University, Shiraz, Iran

3 Department of Exercise Physiology, Kish International Campus, University of Tehran, Kish, Iran

4 Department of Physiology and Pharmacology, Kerman University of Medical Sciences, Kerman, Iran

5 Department of Exercise Physiology, Shiraz University, Shiraz, Iran

6 Department of Exercise Physiology, University of Tehran, Tehran, Iran

Abstract

Objective(s): High-intensity interval training (HIIT) is a shape of interval training that provides ameliorated athletic capacity and has a good effect on health. Resveratrol is a natural polyphenol abundant in grapes and red wine and has been demonstrated to apply various useful health impacts on the body. This research aimed to evaluate the interactive effects of swimming HIIT and resveratrol consumption on SIRTs 3 & 4, NAD+/NADH, AMPK and SOD2 expression in aged rats.
Materials and Methods: In total, forty-five old male albino rats (Wistar) with the age of twenty months were allocated into 5 groups randomly. Control group (Ctrl), Swimming HIIT group (Ex: Exercise), Swimming HIIT with Resveratrol consumption group (R+Ex), Resveratrol consumption group (R) and solvent of resveratrol consumption group (vehicle). R+Ex group accomplished the exercise and consumed resveratrol (10 mg/kg/day, gavage) for 6 weeks.
Results: HIIT & resveratrol significantly increased NAD+/NADH, SOD 2 and AMPK in the aged rats. HIIT increased SIRT3, but resveratrol reduced it. As for SIRT4, HIIT decreased it, while resveratrol positively affected it.
Conclusion: Resveratrol and HIIT, especially their combination, have anti-oxidant and anti-aging effects on the hippocampus of old rats.

Keywords


1. Finch CE, Hayflick L. Handbook of the biology of aging: Van Nostrand Reinhold Co.; 1977.
2. Harman D. Aging: overview. Annals of the New York Academy of Sciences 2001; 928:1-21.
3. Kohn RR. Aging and age-related diseases normal processes. Aging (New York) 1985; 28:1-44.
4. Harman D. Aging: prospects for further increases in the functional life span. Age 1994; 17:119-146.
5. Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science 2005; 307:384-387.
6. Onyango IG, Lu J, Rodova M, Lezi E, Crafter AB, Swerdlow RH. Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim Biophys Acta 2010; 1802:228-234.
7. Guarente L, editor Sirtuins in aging and disease. Cold Spring Harbor symposia on quantitative biology; 2007: Cold Spring Harbor Laboratory Press.
8. Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 2010; 143:802-812.
9. Braidy N, Poljak A, Grant R, Jayasena T, Mansour H, Chan-Ling T, et al. Differential expression of sirtuins in the aging rat brain. Front Cell Neurosci 2015; 9:167.
10. Nasrin N, Wu X, Fortier E, Feng Y, Bare OC, Chen S, et al. SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem 2010; 285:31995-32002.
11. Van de Ven RA, Santos D, Haigis MC. Mitochondrial sirtuins and molecular mechanisms of aging. Trends Mol Med 2017; 23:320-331.
12. Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science 2015; 350:1208-1213.
13. Cheng A, Yang Y, Zhou Y, Maharana C, Lu D, Peng W, et al. Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges. Cell metab 2016; 23:128-142.
14. Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR, et al. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol cell 2013; 50:686-698.
15. Pervaiz S. Resveratrol: From grapevines to mammalian biology. FASEB J 2003; 17:1975-1985.
16. Raval AP, Dave KR, Pérez-Pinzon MA. Resveratrol mimics ischemic preconditioning in the brain. J Cereb Blood Flow  Metab 2006; 26:1141-1147.
17. Demircan C, Gül Z, Büyükuysal RL. High glutamate attenuates S100B and LDH outputs from rat cortical slices enhanced by either oxygen–glucose deprivation or menadione. Neurochem Res 2014; 39:1232-1244.
18. Karuppagounder SS, Pinto JT, Xu H, Chen H-L, Beal MF, Gibson GE. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer’s disease. Neurochem Int 2009; 54:111-118.
19. Kim HJ, Lee KW, Lee HJ. Protective effects of piceatannol against beta‐amyloid–induced neuronal cell death. Ann N Y Acad Sci 2007; 1095:473-482.
20. Mensink M, Hesselink M, Russell A, Schaart G, Sels J, Schrauwen P. Improved skeletal muscle oxidative enzyme activity and restoration of PGC-1 α and PPAR β/δ gene expression upon rosiglitazone treatment in obese patients with type 2 diabetes mellitus. Int J Obes 2007; 31:1302-1310.
21. Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 2011; 14:612-622.
22. Schirmer H, Pereira TCB, Rico EP, Rosemberg DB, Bonan CD, Bogo MR, et al. Modulatory effect of resveratrol on SIRT1, SIRT3, SIRT4, PGC1α and NAMPT gene expression profiles in wild-type adult zebrafish liver. Mol Biol Rep 2012; 39:3281-3289.
23. Amirazodi F, Mehrabi A, Amirazodi M, Parsania S, Rajizadeh MA, Esmaeilpour K. The combination effects of resveratrol and swimming HIIT exercise on novel object recognition and open-field tasks in aged rats. Exp Aging Res 2020; 46:1-23.
24. Nakhaei H, Mogharnasi M, Fanaei H. Effect of swimming training on levels of asprosin, lipid profile, glucose and insulin resistance in rats with metabolic syndrome. Obes Med 2019; 15:100111.
25. Feito Y, Heinrich KM, Butcher SJ, Poston WSC. High-intensity functional training (HIFT): Definition and research implications for improved fitness. Sports 2018; 6:76.
26. Ferrer MD, Tauler P, Sureda A, Tur JA, Pons A. Antioxidant regulatory mechanisms in neutrophils and lymphocytes after intense exercise. J Sports Sci 2009; 27:49-58.
27. Ramos-Filho D, Chicaybam G, de-Souza-Ferreira E, Guerra Martinez C, Kurtenbach E, Casimiro-Lopes G, et al. High intensity interval training (HIIT) induces specific changes in respiration and electron leakage in the mitochondria of different rat skeletal muscles. PloS one 2015; 10:e0131766.
28. Shafiee A, Gaeini A, Soleimani M, Nekouei A, Hadidi V. The effect of eight week of high intensity interval training on expression of mir-210 and ephrinA3 mRNA in soleus muscle healthy male rats. J Arak Uni Med Sci 2014; 17:26-34.
29. Casimiro-Lopes G, Ramos D, Sorenson MM, Salerno VP. Redox balance and mitochondrial glycerol phosphate dehydrogenase activity in trained rats. Eur J Appl Physiol 2012; 112:3839-3846.
30. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013; 153:1194-1217.
31. Rajizadeh MA, Aminizadeh AH, Esmaeilpour K, Bejeshk MA, Sadeghi A, Salimi F. Investigating the effects of Citrullus colocynthis on cognitive performance and anxiety-like behaviors in STZ-induced diabetic rats. Int J Neurosci 2021:1-13.
32. Rajizadeh MA, Najafipour H, Fekr MS, Rostamzadeh F, Jafari E, Bejeshk MA, et al. Anti-inflammatory and anti-oxidative effects of myrtenol in the rats with allergic asthma. Iran J Pharm Res 2019; 18:1488.
33. Desquiret-Dumas V, Gueguen N, Leman G, Baron S, Nivet-Antoine V, Chupin S, et al. Resveratrol induces a mitochondrial complex I-dependent increase in NADH oxidation responsible for sirtuin activation in liver cells. J Biol Chem 2013; 288:36662-36675.
34. Grant R. Resveratrol increases intracellular NAD+ levels through up regulation of the NAD+ synthetic enzyme nicotinamide mononucleotide adenylyltransferase. Nature Precedings 2010:1-1.
35. Goody MF, Henry CA. A need for NAD+ in muscle development, homeostasis, and aging. Skelet Muscle 2018; 8:1-14.
36. Wendt I, Chapman J. Fluorometric studies of recovery metabolism of rat fast-and slow-twitch muscles. Am J Physiol  1976; 230:1644-1649.
37. White AT, Schenk S. NAD+/NADH and skeletal muscle mitochondrial adaptations to exercise. Am J Physiol Endocrinol Metab 2012; 303:E308-E321.
38. Torma F, Gombos Z, Jokai M, Takeda M, Mimura T, Radak Z. High intensity interval training and molecular adaptive response of skeletal muscle. Sports Med Health Sci 2019; 1:24-32.
39. Green H, Jones S, Ball-Burnett M, Farrance B, Ranney D. Adaptations in muscle metabolism to prolonged voluntary exercise and training. J Appl Physiol 1995; 78:138-145.
40. Morales-Alamo D, Ponce-González JG, Guadalupe-Grau A, Rodríguez-García L, Santana A, Cusso R, et al. Critical role for free radicals on sprint exercise-induced CaMKII and AMPKα phosphorylation in human skeletal muscle. J Appl Physiol 2013; 114:566-577.
41. Phillips S, Green H, Tarnopolsky M, Heigenhauser G, Grant S. Progressive effect of endurance training on metabolic adaptations in working skeletal muscle. Am J Physiol 1996; 270:E265-E272.
42. Roldan M, Agerholm M, Nielsen TS, Consitt LA, Søgaard D, Helge JW, et al. Aerobic and resistance exercise training reverses age‐dependent decline in NAD+ salvage capacity in human skeletal muscle. Physiol Rep 2019; 7:14139.
43. Huertas JR, Casuso RA, Agustín PH, Cogliati S. Stay fit, stay young: Mitochondria in movement: The role of exercise in the new mitochondrial paradigm. Oxid Med Cell Longev 2019; 2019:7058350.
44. Vargas-Ortiz K, Pérez-Vázquez V, Macías-Cervantes MH. Exercise and sirtuins: A way to mitochondrial health in skeletal muscle. Int J Mol Sci 2019; 20:2717.
45. Kulkarni SS, Cantó C. The molecular targets of resveratrol. Biochim Biophys Acta 2015; 1852:1114-1123.
46. Lan F, Weikel KA, Cacicedo JM, Ido Y. Resveratrol-induced AMP-activated protein kinase activation is cell-type dependent: lessons from basic research for clinical application. Nutrients 2017; 9:751.
47. Chiang M-C, Nicol CJ, Cheng Y-C. Resveratrol activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced inflammation and oxidative stress. Neurochem Int 2018; 115:1-10.
48. Pineda-Ramírez N, Alquisiras-Burgos I, Ortiz-Plata A, Ruiz-Tachiquín M-E, Espinoza-Rojo M, Aguilera P. Resveratrol activates neuronal autophagy through AMPK in the ischemic brain. Mol Neurobiol 2020; 57:1055-1069.
49. Li Z, Han X. Resveratrol alleviates early brain injury following subarachnoid hemorrhage: Possible involvement of the AMPK/SIRT1/autophagy signaling pathway. Biol Chem 2018; 399:1339-1350.
50. Kristensen DE, Albers PH, Prats C, Baba O, Birk JB, Wojtaszewski JF. Human muscle fibre type‐specific regulation of AMPK and downstream targets by exercise. J Physiol 2015; 593:2053-2069.
51. Casuso RA, Plaza-Díaz J, Ruiz-Ojeda FJ, Aragón-Vela J, Robles-Sanchez C, Nordsborg NB, et al. High-intensity high-volume swimming induces more robust signaling through PGC-1α and AMPK activation than sprint interval swimming in m. triceps brachii. PLoS One 2017; 12:e0185494.
52. Treebak JT, Birk JB, Rose AJ, Kiens B, Richter EA, Wojtaszewski JF. AS160 phosphorylation is associated with activation of α2β2γ1-but not α2β2γ3-AMPK trimeric complex in skeletal muscle during exercise in humans. Am J Physiol Endocrinol Metab 2007; 292:E715-E722.
53. Gibala MJ, McGee SL, Garnham AP, Howlett KF, Snow RJ, Hargreaves M. Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1α in human skeletal muscle. J Appl Physiol 2009; 106:929-934.
54. Fukui M, Choi HJ, Zhu BT. Mechanism for the protective effect of resveratrol against oxidative stress-induced neuronal death. Free Radic Biol Med 2010; 49:800-813.
55. Mathieu L, Costa AL, Le Bachelier C, Slama A, Lebre A-S, Taylor RW, et al. Resveratrol attenuates oxidative stress in mitochondrial Complex I deficiency: Involvement of SIRT3. Free Radic Biol  Med 2016; 96:190-198.
56. Bastianetto S, Ménard C, Quirion R. Neuroprotective action of resveratrol. Biochim Biophys Acta 2015; 1852:1195-1201.
57. Bogdanis G, Stavrinou P, Fatouros I, Philippou A, Chatzinikolaou A, Draganidis D, et al. Short-term high-intensity interval exercise training attenuates oxidative stress responses and improves antioxidant status in healthy humans. Food Chem Toxicol 2013; 61:171-177.
58. Mohar DS, Malik S. The sirtuin system: The holy grail of resveratrol? J Clin Exp Cardiol 2012; 3:216.
59. Tauriainen E, Luostarinen M, Martonen E, Finckenberg P, Kovalainen M, Huotari A, et al. Distinct effects of calorie restriction and resveratrol on diet-induced obesity and fatty liver formation. J Nutr Metab 2011; 2011:525094.
60. Han Y, Zhou S, Coetzee S, Chen A. SIRT4 and its roles in energy and redox metabolism in health, disease and during exercise. Front Physiol 2019; 10:1006.
61. Hart N, Sarga L, Csende Z, Koch LG, Britton SL, Davies KJ, et al. Resveratrol attenuates exercise-induced adaptive responses in rats selectively bred for low running performance. Dose Response 2013; 12:57-71.
62. Hart N, Sarga L, Csende Z, Koltai E, Koch LG, Britton SL, et al. Resveratrol enhances exercise training responses in rats selectively bred for high running performance. Food Chem Toxicol 2013; 61:53-59.
63. Chen Y-R, Fang S-R, Fu Y-C, Zhou X-H, Xu M-Y, Xu W-C. Calorie restriction on insulin resistance and expression of SIRT1 and SIRT4 in rats. Biochem Cell Biol 2010; 88:715-722.
64. Dean D. Daugaard JR, Young ME, Saha A, Vavvas D, Asp S, et al. Exercise diminishes the activity of acetyl-CoA carboxylase in human muscle. Diabetes 2000; 49:1295-1300.
65. Karvinen S, Silvennoinen M, Vainio P, Sistonen L, Koch LG, Britton SL, et al. Effects of intrinsic aerobic capacity, aging and voluntary running on skeletal muscle sirtuins and heat shock proteins. Exp Gerontol 2016; 79:46-54.
66. Radak Z, Koltai E, Taylor AW, Higuchi M, Kumagai S, Ohno H, et al. Redox-regulating sirtuins in aging, caloric restriction, and exercise. Free Radic Biol Med 2013; 58:87-97.
67. Acs Z, Bori Z, Takeda M, Osvath P, Berkes I, Taylor AW, et al. High altitude exposure alters gene expression levels of DNA repair enzymes, and modulates fatty acid metabolism by SIRT4 induction in human skeletal muscle. Respir physiol Neurobiol 2014; 196:33-37.
68. Palacios OM, Carmona JJ, Michan S, Chen KY, Manabe Y, Ward III JL, et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1α in skeletal muscle. Aging (Albany NY) 2009; 1:771.
69. Hokari F, Kawasaki E, Sakai A, Koshinaka K, Sakuma K, Kawanaka K. Muscle contractile activity regulates Sirt3 protein expression in rat skeletal muscles. J Appl Physiol 2010; 109:332-340.
70. Muñoz A, Corrêa CL, Lopez-Lopez A, Costa-Besada MA, Diaz-Ruiz C, Labandeira-Garcia JL. Physical exercise improves aging-related changes in angiotensin, IGF-1, SIRT1, SIRT3, and VEGF in the Substantia nigra. J Gerontol A Biol Sci Med Sci 2018; 73:1594-1601.
71. Bagul PK, Katare PB, Bugga P, Dinda AK, Banerjee SK. SIRT-3 modulation by resveratrol improves mitochondrial oxidative phosphorylation in diabetic heart through deacetylation of TFAM. Cells 2018; 7:235.
72. Moraes DS, Moreira DC, Andrade JMO, Santos SHS. Sirtuins, brain and cognition: A review of resveratrol effects. IBRO Rep 2020; 9:46-51.
73. Kincaid B, Bossy-Wetzel E. Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Front Aging Neurosci 2013; 5:48.
74. Tabrizi R, Tamtaji OR, Lankarani KB, Akbari M, Dadgostar E, Dabbaghmanesh MH, et al. The effects of resveratrol intake on weight loss: A systematic review and meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr 2020; 60:375-390.
75. Belviranlı M, Okudan N. Exercise training protects against aging-induced cognitive dysfunction via activation of the hippocampal PGC-1α/FNDC5/BDNF pathway. Neuromolecul Med 2018; 20:386-400.
76. Wang G-W, Cao J, Wang X-Q. Effects of ethanol extract from Bidens pilosa L. on spontaneous activity, learning and memory in aged rats. Exp Gerontol 2019; 125:110651.
77. Gallagher M, Burwell R, Burchinal M. Severity of spatial learning impairment in aging: Development of a learning index for performance in the Morris water maze. Behav Neurosci 2015; 129:540-548.
78. Ruan B, Wang R, Yang Y-J, Wang D-F, Wang J-W, Zhang C-C, et al. Improved effects of saponins from Panax japonicus on decline of cognitive function in natural aging rats via NLRP3 inflammasome pathway. Zhongguo Zhong Yao Za Zhi 2019; 44:344-349.
79. Lehmann M, Zappa-Villar MF, García MG, Mazzolini G, Canatelli-Mallat M, Morel GR, et al. Umbilical cord cell therapy improves spatial memory in aging rats. Stem Cell Rev Rep 2019; 15:612-617.
80. Shukitt-Hale B, McEwen JJ, Szprengiel A, Joseph JA. Effect of age on the radial arm water maze-a test of spatial learning and memory. Neurobiol Aging 2004; 25:223-229.
81. Qiu L-L, Pan W, Luo D, Zhang G-F, Zhou Z-Q, Sun X-Y, et al. Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca 2+/calpain might contribute to postoperative cognitive dysfunction in aging mice. J Neuroinflammation 2020; 17:1-15.