Moderate aerobic exercise training decreases middle-aged induced pathologic cardiac hypertrophy by improving Klotho expression, MAPK signaling pathway and oxidative stress status in Wistar rats

Document Type : Original Article

Authors

1 Department of Physical Education and Sport Science, Jolfa Branch, Islamic Azad University, Jolfa, Iran

2 Department of Physical Education and Sport Science, University of Mohaghegh Ardabili, Ardabil, Iran

3 Department of Kinesiology, College of Agriculture, Health and Natural Resources, University of Connecticut, Connecticut, USA

Abstract

Objective(s): This study aimed to investigate the effect of aerobic training on serum levels of Klotho, cardiac tissue levels of H2O2 and phosphorylation of ERK1/2 and P38 as well as left ventricular internal diameter (LVID), the left ventricle wall thickness (LVWT) and fibrosis in middle-aged rats.
Materials and Methods: Forty wistar rats, including young rats (n=10, 4 month-old) and middle-aged rats (n=30, 13-15 months-old) were enrolled in this experimental study. The all young and 10 middle-aged rats were sacrificed (randomly) under deep anesthesia without any exercise training as normal young control and normal middle-aged control respectively. The remaining 20 middle-aged rats participated in 4 (n=10) or 8-week (n=10) aerobic exercise training.
Results: There were significant differences in the plasmatic Klotho levels and the heart tissue levels of phosphorylated-ERK1/2 (p-ERK1/2), P-P38 and H2O2, LVWT, LVID and fibrosis between young and middle-aged rats (P=0.01). Plasmatic Klotho level was significantly increased after eight weeks training (P=0.011). Also, p-ERK1/2 was significantly decreased after eight weeks and p-P38 was significantly decreased in the fourth (P=0.01) and eight weeks of training (P=0.01). A similar decrease was reported for aging-induced H2O2 in the fourth (P=0.016) and eighth weeks (P=0.001). LVID was significantly increased in eight weeks, but LVWT and fibrosis was significantly reduced in the eighth week (P=0.011, P=0.028, P=0.001 respectively).
Conclusion: Moderate aerobic training attenuates aging-induced pathological cardiac hypertrophy at least partially by restoring the Klotho levels, attenuating oxidative stress, and reduction in the phosphorylation of ERK1/2, P38 and fibrosis.

Keywords

Main Subjects


1. Aikawa R, Nagai T, Tanaka M, Zou Y, Ishihara T, Takano H, et al. Reactive oxygen species in mechanical stress-induced cardiac hypertrophy. Biochem Biophys Res Commun 2001; 289:901-907.
2. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114:763-776.
3. Fernandes T, Baraúna VG, Negrão CE, Phillips MI, Oliveira EM. Aerobic exercise training promotes physiological cardiac remodeling involving a set of microRNAs. Am J Physiol Heart Circ Physiol 2015; 309:H543-H552.
4. McMullen JR, Jennings GL. Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. Clin Exp Pharmacol Physiol 2007; 34:255-262.
5. Chelliah RK, Senior R. Pathological and physiological left ventricular hypertrophy: echocardiography for differentiation. Future Cardiol 2009; 5:495-502.
6. Barry SP DS, Townsend PA. Molecular regulation of cardiac hypertrophy. Int J Biochem Cell Biol 2008; 40:2023-2039.
7. Hu MC, Shi M, Cho HJ, Adams-Huet B, Paek J, Hill K, et al. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol 2015; 26:1290-1302.
8. White KE, Evans WE, O’Riordan JL, Speer MC, Econs MJ, Lorenz-Depiereux B, et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; 26:345-348.
9. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444:770-774.
10. Razzaque MS. The FGF23–Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol 2009; 5:611-619.
11. Yoshida T, Fujimori T, Nabeshima Y-I. Mediation of unusually high concentrations of 1, 25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1α-hydroxylase gene. Endocrinology 2002; 143:683-689.
12. Nakatani T, Sarraj B, Ohnishi M, Densmore MJ, Taguchi T, Goetz R, et al. In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23)-mediated regulation of systemic phosphate homeostasis. FASEB J 2009; 23:433-441.
13. Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y-i. Identification of the HumanKlothoGene and Its Two Transcripts Encoding Membrane and SecretedKlothoProtein. Biochem Biophys Res Commun 1998; 242:626-630.
14. Xiao N-M, Zhang Y-M, Zheng Q, Gu J. Klotho is a serum factor related to human aging. Chin Med J (Engl) 2004; 117:742-747.
15. Song S, Gao P, Xiao H, Xu Y, Si LY. Klotho suppresses cardiomyocyte apoptosis in mice with stress-induced cardiac injury via downregulation of endoplasmic reticulum stress.  PLoS One 2013; 8:e82968.
16. Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002; 298:1911-1912.
17. Pearson G, Robinson F, Beers Gibson T, Xu B-e, Karandikar M, Berman K, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions 1. Endocr Rev 2001; 22:153-183.
18. Qi M, Elion EA. MAP kinase pathways. J Cell Sci 2005; 118:3569-3572.
19.Kehat I, Molkentin JD. Extracellular signal‐regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy. Ann N Y Acad Sci 2010; 1188:96-102.
20. Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, et al. The MEK1–ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J 2000; 19:6341-6350.
21. Bueno OF, Molkentin JD. Involvement of extracellular signal-regulated kinases 1/2 in cardiac hypertrophy and cell death. Circ Res 2002; 91:776-781.
22. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol 2004; 5:875-885.
23. Shaul YD, Seger R. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta 2007; 1773:1213-1226.
24. Zechner D, Thuerauf DJ, Hanford DS, McDonough PM, Glembotski CC. A role for the p38 mitogen-activated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression. J Cell Biol 1997; 139:115-127.
25. Li M, Georgakopoulos D, Lu G, Hester L, Kass DA, Hasday J, et al. P38 MAP kinase mediates inflammatory cytokine induction in cardiomyocytes and extracellular matrix remodeling in heart. Circulation 2005; 111:2494-2502.
26. Martindale JJ, Wall JA, Martinez-Longoria DM, Aryal P, Rockman HA, Guo Y, et al. Overexpression of mitogen-activated protein kinase kinase 6 in the heart improves functional recovery from ischemia in vitro and protects against myocardial infarction in vivo. J Biol Chem 2005; 280:669-676.
27. Nishida K, Yamaguchi O, Hirotani S, Hikoso S, Higuchi Y, Watanabe T, et al. P38α mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload. Mol Cell Biol 2004; 24:10611-10620.
28. Streicher JM, Ren S, Herschman H, Wang Y. MAPK-activated protein kinase-2 in cardiac hypertrophy and cyclooxygenase-2 regulation in heart. Circ Res 2010; 106:1434-1443.
29. Garciarena CD, Pinilla OA, Nolly MB, Laguens RP, Escudero EM, Cingolani HE, et al. Endurance training in the spontaneously hypertensive rat conversion of pathological into physiological cardiac hypertrophy. Hypertension 2009; 53:708-714.
30. Matsubara T, Miyaki A, Akazawa N, Choi Y, Ra S-G, Tanahashi K, et al. Aerobic exercise training increases plasma Klotho levels and reduces arterial stiffness in postmenopausal women. Am J Physiol Heart Circ Physiol 2014; 306:H348-H355.
31. Watanabe K-i, Ma M, Hirabayashi K-i, Gurusamy N, Veeraveedu PT, Prakash P, et al. Swimming stress in DN 14-3-3 mice triggers maladaptive cardiac remodeling: role of p38 MAPK. Am J Physiol Heart Circ Physiol 2007; 292:H1269-H1277.
32. Miyachi M, Yazawa H, Furukawa M, Tsuboi K, Ohtake M, Nishizawa T, et al. Exercise training alters left ventricular geometry and attenuates heart failure in dahl salt-sensitive hypertensive rats. Hypertension 2009; 53:701-707.
33. Nam C-W, Lee J-H, Jang S-H. Effects of treadmill speed on the knee angle and stance time of white rats with knee osteoarthritis according to the treadmill speed. J Phys Ther Sci 2016; 28:3003-3006.
34. Khani M, Motamedi P, Dehkhoda MR, Nikukheslat SD, Karimi P. Effect of thyme extract supplementation on lipid peroxidation, antioxidant capacity, PGC-1α content and endurance exercise performance in rats. J Int Soc Sports Nutr 2017; 14:1-8.
35. Burchfield JS, Xie M, Hill JA. Pathological ventricular remodeling. Circulation 2013; 128:388-400.
36. Liao P-H, Hsieh DJ-Y, Kuo C-H, Day C-H, Shen C-Y, Lai C-H, et al. Moderate exercise training attenuates aging-induced cardiac inflammation, hypertrophy and fibrosis injuries of rat hearts. Oncotarget 2015; 6:35383-35394.
37. Dedkov EI, Oak K, Christensen LP, Tomanek RJ. Coronary vessels and cardiac myocytes of middle-aged rats demonstrate regional sex-specific adaptation in response to postmyocardial infarction remodeling. Biol Sex Differ 2014; 5:1-14.
38. Hu MC, Kuro-o M, Moe OW. Klotho and chronic kidney disease.  Contrib Nephrol 2013;180:47-63.
39. Kuro-o M. Klotho and the aging process. Korean J Intern Med 2011; 26:113-122.
40. Stevens LA, Li S, Wang C, Huang C, Becker BN, Bomback AS, et al. Prevalence of CKD and comorbid illness in elderly patients in the United States: results from the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis 2010; 55:S23-S33.
41. Zoccali C, Kramer A, Jager KJ. Epidemiology of CKD in Europe: an uncertain scenario. Nephrol Dial Transplant 2010; 25:1731-1733.
42. Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 2005; 112:2627-2633.
43. Bian A, Neyra JA, Zhan M, Hu MC. Klotho, stem cells, and aging. Clin Interv Aging 2014; 10:1233-1243.
44. Mencke R, Olauson H, Hillebrands J-L. Effects of Klotho on fibrosis and cancer: A renal focus on mechanisms and therapeutic strategies. Adv Drug Deliv Rev 2017; 121:85-100.
45. Hsieh C, Kuro-o M, Rosenblatt KP, Brobey R, Papaconstantinou J. The ASK1-Signalosome regulates p38 MAPK activity in response to levels of endogenous oxidative stress in the Klotho mouse models of aging. Aging 2010; 2:597-611.
46. Moens AL, Takimoto E, Tocchetti CG, Chakir K, Bedja D, Cormaci G, et al. Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin efficacy of recoupling nitric oxide synthase as a therapeutic strategy. circulation 2008; 117:2626-2636.
47. Aikawa R, Nagai T, Tanaka M, Zou Y, Ishihara T, Takano H, et al. Reactive oxygen species in mechanical stress-induced cardiac hypertrophy. Biochem Biophys Res Commun 2001; 289:901-907.
48. Sabri A, Byron KL, Samarel AM, Bell J, Lucchesi PA. Hydrogen peroxide activates mitogen-activated protein kinases and Na+-H+ exchange in neonatal rat cardiac myocytes. Circ Res 1998; 82:1053-1062.
49. Castillo Garzón MJ, Ruiz JR, Ortega Porcel FB, Gutiérrez Á. Anti-aging therapy through fitness enhancement.  Clin Interv Aging 2006; 1: 213–220.
50. Zhang R, Zheng F. PPAR-γ and aging: one link through klotho? Kidney international 2008; 74:702-704.
51. Xu Y, Sun Z. Molecular basis of Klotho: from gene to function in aging. Kidney Int 2015; 36:174-193.
52. Baghaiee B, Teixeira AB, Tartibian B. Moderate aerobic exercise increases SOD-2 gene expression and decreases leptin and malondialdehyde in middle-aged men. Sci Sport 2016; 31:e55-e63.
53. Yu L, Meng W, Ding J, Cheng M. Klotho inhibits angiotensin II-induced cardiomyocyte hypertrophy through suppression of the AT 1 R/beta catenin pathway. Biochem Biophys Res Commun 2016; 473:455-461.
54. de Borst MH, Vervloet MG, ter Wee PM, Navis G. Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease. J Am Soc Nephrol 2011; 22:1603-1609.
55. Matsushima S, Sadoshima J. The role of sirtuins in cardiac disease. Am J Physiol Heart Circ Physiol 2015; 309:H1375-H1389.
56. Maulik SK, Kumar S. Oxidative stress and cardiac hypertrophy: a review. Toxicol Mech Methods 2012; 22:359-366.
57. Liang Q, Molkentin JD. Redefining the roles of p38 and JNK signaling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models. J Mol Cell Cardiol 2003; 35:1385-1394.
58. Petrich BG, Eloff BC, Lerner DL, Kovacs A, Saffitz JE, Rosenbaum DS, et al. Targeted activation of c-Jun N-terminal kinase in vivo induces restrictive cardiomyopathy and conduction defects. J Biol Chem 2004; 279:15330-15338.
59. Javadov S, Jang S, Agostini B. Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: therapeutic perspectives. Pharmacol Ther 2014; 144:202-225.
60. Junttila MR, Li S-P, Westermarck J. Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J 2008; 22:954-965.
61.Lee Y-J, Cho H-N, Soh J-W, Jhon GJ, Cho C-K, Chung H-Y, et al. Oxidative stress-induced apoptosis is mediated by ERK1/2 phosphorylation. Exp Cell Res 2003; 291:251-266.
62. Hu MC, Kuro-o M, Moe OW. Secreted klotho and chronic kidney disease.  Adv Exp Med Biol 2012;728:126-57.
63. Degaspari S, Tzanno-Martins CB, Fujihara CK, Zatz R, Branco-Martins JP, Viel TA, et al. Altered KLOTHO and NF-κB-TNF-α signaling are correlated with nephrectomy-induced cognitive impairment in rats. PloS one 2015; 10:1-22.