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Intrauterine growth restriction increases circulating mitochondrial DNA and Toll-like receptor 9 expression in adult offspring: could aerobic training counteract these adaptations?

  • V. Oliveira (a1), S. D. Silva Junior (a2), M. H. C. de Carvalho (a3), E. H. Akamine (a3), L. C. Michelini (a2) and M. C. Franco (a1) (a4)...

Abstract

It has been demonstrated that intrauterine growth restriction (IUGR) can program increase cardiometabolic risk. There are also evidences of the correlation between IUGR with low-grade inflammation and, thus can contribute to development of several cardiometabolic comorbidities. Therefore, we investigated the influence of IUGR on circulating mitochondrial DNA (mtDNA)/Toll-like receptor 9 (TLR9) and TNF-α expression in adult offspring. Considering that the aerobic training has anti-inflammatory actions, we also investigated whether aerobic training would improve these inflammatory factors. Pregnant Wistar rats received ad libitum or 50% of ad libitum diet throughout gestation. At 8 weeks of age, male offspring from both groups were randomly assigned to control, trained control, restricted and trained restricted. Aerobic training protocol was performed on a treadmill and after that, we evaluated circulating mtDNA, cardiac protein expression of TLR9, plasma and cardiac TNF-α levels, and left ventricle (LV) mass. We found that IUGR promoted an increase in the circulating mtDNA, TLR9 expression and plasma TNF-α levels. Further, our results revealed that aerobic training can restore mtDNA/TLR9 content and plasma levels of TNF-α among restricted rats. The cardiac TNF-α content and LV mass were not influenced either by IUGR or aerobic training. In conclusion, IUGR can program mtDNA/TLR9 content, which may lead to high levels of TNF-α. However, aerobic training was able to normalize these alterations. These findings evidenced that the association of IUGR and aerobic training seems to exert an important interaction effect regarding pro-inflammatory condition and, aerobic training may be used as a strategy to reduce deleterious adaptations in IUGR offspring.

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Corresponding author

*Address for correspondence: M. do Carmo Franco, School of Medicine, Division of Nephrology, Federal University of São Paulo, Rua Botucatu, 703-São Paulo, SP 04023-062, Brazil.(Email maria.franco@unifesp.br)

References

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1. Barker, DJ, Bull, AR, Osmond, C, Simonds, SJ. Fetal and placental size and risk of hypertension in adult life. BMJ. 1990; 301, 259262.
2. Gluckman, PD, Hanson, MA, Pinal, C. The developmental origins of adult disease. Matern Child Nutr. 2005; 1, 130141.
3. Franco, M, Akamine, EH, Di Marco, GS, et al. NADPH oxidase and enhanced superoxide generation in the intrauterine undernourished rats: involvement of the renin-angiotensin system. Cardiovasc Res. 2003; 59, 767775.
4. Sato, S, Mukai, Y, Norikura, T. Maternal low-protein diet suppresses vascular and renal endothelial nitric oxide synthase phosphorylation in rat offspring independent of a postnatal fructose diet. J Dev Orig Health Dis. 2011; 3, 168175.
5. Chandra, RK. Antibody formation in first and second generation offspring of nutritionally deprived rats. Science. 1975; 190, 289290.
6. Moscatelli, P, Bricarelli, FG, Piccinini, A, et al. Defective immunocompetence for foetal malnutrition. Helv Paediatr Acta. 1976; 21, 241247.
7. Campos, SM, de Oliveira, VL, Lessa, L, et al. Maternal immunomodulation of the offspring’s immunological system. Immunobiology. 2014; 11, 813821.
8. Guzik, TJ, Hoch, NE, Brown, KA, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med. 2007; 10, 24492460.
9. Bomfim, GF, Dos Santos, RA, Oliveira, MA, et al. Toll-like receptor 4 contributes to blood pressure regulation and vascular contraction in spontaneously hypertensive rats. Clin Sci (Lond). 2012; 11, 535543.
10. McCarthy, CG, Wenceslau, CF, Goulopoulou, S, et al. Circulating mitochondrial DNA and toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. Cardiovasc Res. 2015; 1, 119130.
11. Frantz, S, Ertl, G, Bauersachs, J. Mechanisms of disease: toll-like receptors in cardiovascular disease. Nat Clin Pract Cardiovasc Med. 2007; 4, 444454.
12. Equils, O, Singh, S, Karaburun, S, et al. Intra-uterine growth restriction downregulates the hepatic toll like receptor-4 expression and function. Clin Dev Immunol. 2005; 1, 5966.
13. Han, F, Hu, L, Xuan, Y, et al. Effects of high nutrient intake on the growth performance, intestinal morphology and immune function of neonatal intra-uterine growth-retarded pigs. Br J Nutr. 2013; 10, 18191827.
14. Chadio, S, Katsafadou, A, Kotsampasi, B, et al. Effects of maternal undernutrition during late gestation and/or lactation on colostrum synthesis and immunological parameters in the offspring. Reprod Fertil Dev. 2016; 3, 384393.
15. Zhang, Q, Raoof, M, Chen, Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010; 7285, 104107.
16. Berezin, AE. Circulating cell-free mitochondrial DNA as biomarker of cardiovascular risk: new challenges of old findings. Angiology. 2015; 3, 161.
17. Pescatello, LS, Franklin, BA, Fagard, R, et al. American College of Sports Medicine position stand: exercise and hypertension. Med Sci Sports Exerc. 2004; 36, 533553.
18. Moita, L, Lustosa, MF, Silva, AT, et al. Moderate physical training attenuates the effects of perinatal undernutrition on the morphometric of the splenic lymphoid follicles in endotoxemic adult rats. Neuroimmunomodulation. 2011; 2, 103110.
19. Oliveira, V, Akamine, EH, Carvalho, MHC, et al. Influence of aerobic training on the reduced vasoconstriction to angiotensin II in rats exposed to intrauterine growth restriction: possible role of oxidative stress and AT2 receptor of angiotensin II. PLoS ONE. 2014; 11, e113035.
20. Reyes, LM, Morton, JS, Kirschenman, R, et al. Vascular effects of aerobic exercise training in rat adult offspring exposed to hypoxia-induced intrauterine growth restriction. J Physiol. 2015; 593, 19131929.
21. Romero-Calvo, I, Ocón, B, Martínez-Moya, P, et al. Reversible Ponceau staining as a loading control alternative to actin in Western blots. Anal Biochem. 2010; 2, 318320.
22. Liu, J, Cai, X, Xie, L, et al. Circulating cell free mitochondrial DNA is a biomarker in the development of coronary heart disease in the patients with type 2 diabetes. Clin Lab. 2015; 7, 661667.
23. Park, HK, Jin, CJ, Cho, YM, et al. Changes of mitochondrial DNA content in the male offspring of protein-malnourished rats. Ann N Y Acad Sci. 2004; 1011, 205216.
24. Beauchamp, B, Ghosh, S, Dysart, MW, et al. Low birth weight is associated with adiposity, impaired skeletal muscle energetics and weight loss resistance in mice. Int J Obes (Lond). 2015; 4, 702711.
25. Lee, YY, Lee, HJ, Lee, SS, et al. Taurine supplementation restored the changes in pancreatic islet mitochondria in the fetal protein-malnourished rat. Br J Nutr. 2011; 8, 11981206.
26. Miquel, J. An update on the mitochondrial-DNA mutation hypothesis of cell aging. Mutat Res. 1992; 3–6, 209216.
27. Nasi, M, Cristani, A, Pinti, M, et al. Decreased circulating mtDNA levels in professional male volleyball players. Int J Sports Physiol Perform. 2016; 1, 116121.
28. Shockett, PE, Khanal, J, Sitaula, A, et al. Plasma cell-free mitochondrial DNA declines in response to prolonged moderate aerobic exercise. Physiol Rep. 2016; 1, pii: e12672.
29. Wang, H, Bei, Y, Lu, Y, et al. Exercise prevents cardiac injury and improves mitochondrial biogenesis in advanced diabetic cardiomyopathy with PGC-1α and Akt activation. Cell Physiol Biochem. 2015; 6, 21592168.
30. Jafari, A, Hosseinpourfaizi, MA, Houshmand, M, et al. Effect of aerobic exercise training on mtDNA deletion in soleus muscle of trained and untrained Wistar rats. Br J Sports Med. 2005; 8, 517520.
31. Ma, Y, He, M, Qiang, L. Exercise therapy downregulates the overexpression of TLR4, TLR2, MyD88 and NF-κB after cerebral ischemia in rats. Int J Mol Sci. 2013; 2, 37183733.
32. Oliveira, AG, Carvalho, BM, Tobar, N, et al. Physical exercise reduces circulating lipopolysaccharide and TLR4 activation and improves insulin signaling in tissues of DIO rats. Diabetes. 2011; 3, 784796.
33. Landgraf, MA, Landgraf, RG, Silva, RC, et al. Intrauterine undernourishment alters TH1/TH2 cytokine balance and attenuates lung allergic inflammation in Wistar rats. Cell Physiol Biochem. 2012; 3, 552562.
34. Riddle, ES, Campbell, MS, Lang, BY, et al. Intrauterine growth restriction increases TNF α and activates the unfolded protein response in male rat pups. J Obes. 2014; 2014, 829862.
35. Gleeson, M, McFarlin, B, Flynn, M. Exercise and Toll-like receptors. Exerc Immunol Rev. 2006; 12, 3453.
36. Harvey, TJ, Murphy, RM, Morrison, JL, et al. Maternal nutrient restriction alters Ca2+ handling properties and contractile function of isolated left ventricle bundles in male but not female juvenile rats. PLoS ONE. 2015; 9, e0138388.
37. Muaku, SM, Thissen, JP, Gerard, G, et al. Postnatal catch-up growth induced by growth hormone and insulin-like growth factor-I in rats with intrauterine growth retardation caused by maternal protein malnutrition. Pediatr Res. 1997; 3, 370377.
38. Menendez-Castro, C, Toka, O, Fahlbusch, F, et al. Impaired myocardial performance in a normotensive rat model of intrauterine growth restriction. Pediatr Res. 2014; 6, 697706.

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