Effects of Physical Exercise on the P38MAPK/REDD1/14-3-3 Pathways in the Myocardium of Diet-Induced Obesity Rats

B. L. S. Pieri; D. R. Souza; T. F. Luciano; S. O. Marques; J. R. Pauli; A. S. R. Silva; E. R. Ropelle; R. A. Pinho; F. S. Lira; C. T. De Souza

doi:10.1055/s-0034-1371824

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2014; 46(09): 621-627
DOI: 10.1055/s-0034-1371824

Endocrine Research

Effects of Physical Exercise on the P38MAPK/REDD1/14-3-3 Pathways in the Myocardium of Diet-Induced Obesity Rats

Authors

B. L. S. Pieri

¹Laboratory of Exercise Biochemistry and Physiology, Health Sciences Unit, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
D. R. Souza

¹Laboratory of Exercise Biochemistry and Physiology, Health Sciences Unit, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
T. F. Luciano

¹Laboratory of Exercise Biochemistry and Physiology, Health Sciences Unit, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
S. O. Marques

¹Laboratory of Exercise Biochemistry and Physiology, Health Sciences Unit, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
J. R. Pauli

²Faculty of Applied Sciences, University of Campinas – UNICAMP, Limeira, São Paulo, Brazil
A. S. R. Silva

³School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
E. R. Ropelle

²Faculty of Applied Sciences, University of Campinas – UNICAMP, Limeira, São Paulo, Brazil
R. A. Pinho

¹Laboratory of Exercise Biochemistry and Physiology, Health Sciences Unit, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
F. S. Lira

⁴Immunometabolism Research Group, Department of Physical Education, Universidade Estadual Paulista, UNESP, Presidente Prudente, São Paulo, Brazil
C. T. De Souza

¹Laboratory of Exercise Biochemistry and Physiology, Health Sciences Unit, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

Abstract

Obesity is associated with myocardial insulin resistance and impairment of the mammalian target of rapamycin (mTOR) signaling pathway. The activation of the mTOR cascade by exercise has been largely shown in skeletal muscle, but insufficiently analyzed in myocardial tissue. In addition, little is known regarding the mTOR upstream molecules in the hearts of obese animals and even less about the role of exercise in this process. Thus, the present study was aimed to evaluate the effects of physical exercise on P38 Mitogen-Activated Protein Kinase (P38MAPK) phosphorylation and the REDD1 (regulated in development and DNA damage responses 1) and 14-3-3 protein levels in the myocardium of diet-induced obesity (DIO) rats. After achievement of DIO and insulin resistance, Wistar rats were divided in 2 groups: sedentary obese rats and obese rats performed treadmill running (50-min/day, 5 days per week velocity of 1.0 km/h for 2 months). Forty-eight hours after the final physical exercise, the rats were killed, and the myocardial tissue was removed for Western blot analysis. DIO increased the REDD1 protein levels and reduced the 14-3-3 protein levels and P38MAPK, mTOR, P70S6k (p70 ribosomal S6 protein kinase), and 4EBP1 (4E-binding protein-1) phosphorylation. Interestingly, physical exercise reduced the REDD1 protein levels and increased the 14-3-3 protein levels and P38MAPK, mTOR, P70S6k, and 4EBP1 phosphorylation. Moreover, exercise increased the REDD1/14-3-3 association in the heart. Our results indicate that the phospho-P38MAPK, REDD1, and 14-3-3 protein levels were reduced in the myocardium of obese rats and that physical exercise increased the protein levels of these molecules.

Key words

obesity - mTOR phosphorylation - REDD1 - 14-3-3 protein - physical activity

Full Text

References

References
1 Adams KF, Schatzkin A, Harris TB, Mouw T, Ballard-Barbash R, Hollenbeck A, Leitzmann MF. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med 2006; 355: 763778
2 Lakka TA, Lakka HM, Salonen R, Kaplan GA, Salonen JT. Abdominal obesity is associated with accelerated progression of carotid atherosclerosis in men. Atherosclerosis 2001; 154: 497-504
3 Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart failure. N Engl J Med 2002; 347: 305-313
4 Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72: 219-246
5 Golbidi S, Laher I. Exercise and the cardiovascular system. Cardiol Res Pract 2012; 2012: 210852
6 Rolfe M, McLeod LE, Pratt PF, Proud CG. Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2). Biochem J 2005; 388: 973-984
7 Yang Q, Guan KL. Expanding mTOR signaling. Cell Res 2007; 17: 666-681
8 Vega-Rubin-de-Celis S, Abdallah Z, Kinch L, Grishin NV, Brugarolas J, Zhang X. Structural analysis and functional implications of the negative mTORC1 regulator REDD1. Biochemistry 2010; 49: 2491-2501
9 Hernández G, Lal H, Fidalgo M, Guerrero A, Zalvide J, Force T, Pombo CM. A novel cardioprotective p38-MAPK/mTOR pathway. Exp Cell Res 2011; 317: 2938-2949
10 Kleppe R, Martinez A, Døskeland SO, Haavik J. The 14-3-3 proteins in regulation of cellular metabolism. Semin Cell Dev Biol 2011; 22: 713-719
11 Autieri MV, Haines DS, Romanic AM, Ohlstein EH. Expression of 14-3-3 gamma in injured arteries and growth factor- and cytokine-stimulated human vascular smooth muscle cells. Cell Growth Differ 1996; 7: 1453-1460
12 Chen HP, He M, Xu YL, Huang QR, Zeng GH, Liu D, Liao ZP. Anoxic preconditioning up-regulates 14-3-3 protein expression in neonatal rat cardiomyocytes through extracellular signal-regulated protein kinase 1/2. Life Sci 2007; 81: 372-379
13 He M, Zhang J, Shao L, Huang Q, Chen J, Chen H, Chen X, Liu D, Luo Z. Upregulation of 14-3-3 isoforms in acute rat myocardial injuries induced by burn and lipopolysaccharide. Clin Exp Pharmacol Physiol 2006; 33: 374-380
14 DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 2008; 22: 239-251
15 Igarashi M, Yamaguchi H, Hirata A, Daimon M, Tominaga M, Kato T. Insulin activates p38 mitogen-activated protein (MAP) kinase via a MAP kinase kinase (MKK) 3/MKK 6 pathway in vascular smooth muscle cells. Eur J Clin Invest 2000; 30: 668-677
16 Da Silva AS, Pauli JR, Ropelle ER, Oliveira AG, Cintra DE, de Souza CT, Velloso LA, Carvalheira JB, Saad MJ. Exercise intensity, inflammatory signaling, and insulin resistance in obese rats. Med Sci Sports Exerc 2010; 42: 2180-2188
17 Marinho R, Ropelle ER, Cintra DE, De Souza CT, Da Silva AS, Bertoli FC, Colantonio E, D’Almeida V, Pauli JR. Endurance exercise training increases APPL1 expression and improves insulin signaling in the hepatic tissue of diet-induced obese mice, independently of weight loss. J Cell Physiol 2012; 227: 2917-2926
18 de Moura LP, Souza Pauli LS, Cintra DE, De Souza CT, da Silva AS, Marinho R, de Melo MA, Ropelle ER, Pauli JR. Acute exercise decreases PTP-1B protein level and improves insulin signaling in the liver of old rats. Immun Ageing 2013; 10: 8
19 Medeiros C, Frederico MJ, da Luz G, Pauli JR, Silva AS, Pinho RA, Velloso LA, Ropelle ER, De Souza CT. Exercise training reduces insulin resistance and upregulates the mTOR/p70S6k pathway in cardiac muscle of diet-induced obesity rats. J Cell Physiol 2011; 226: 666-674
20 De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 2005; 146: 4189-4191
21 Barbosa VA, Luciano TF, Vitto MF, Cesconetto PA, Marques SO, Souza DR, Bom K, Pimentel GD, Katashima CK, Ropelle ER, Pinho RA, De Souza CT. Exercise training plays cardioprotection through the oxidative stress reduction in obese rats submitted to myocardial infarction. Int J Cardiol 2012; 157: 422-424
22 Da Luz G, Frederico MJ, da Silva S, Vitto MF, Cesconetto PA, de Pinho RA, Pauli JR, Silva AS, Cintra DE, Ropelle ER, De Souza CT. Endurance exercise training ameliorates insulin resistance and reticulum stress in adipose and hepatic tissue in obese rats. Eur J Appl Physiol 2011; 111: 2015-2023
23 Pauli RJ, Cintra DE, De Souza CT, Ropelle ER. New mechanisms by which physical exercise improves insulin resistance in the skeletal muscle. Arq Bras Endocrinol Metab 2009; 53: 399-408
24 Bodine SC. mTOR signaling and the molecular adaptation to resistance exercise. Med Sci Sports Exerc 2006; 38: 1950-1957
25 Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, Hara K, Tanaka N, Avruch J, Yonezawa K. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem 2003; 278: 15461-15464
26 Cully M, Genevet A, Warne P, Treins C, Liu T, Bastien J, Baum B, Tapon N, Leevers SJ, Downward J. A role for p38 stress-activated protein kinase in regulation of cell growth via TORC1. Mol Cell Biol 2010; 30: 481-495
27 Nellist M, Goedbloed MA, Halley DJ. Regulation of tuberous sclerosis complex (TSC) function by 14-3-3 proteins. Biochem Soc Trans 2003; 31: 587-591