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The placental mTOR-pathway: correlation with early growth trajectories following intrauterine growth restriction?

Published online by Cambridge University Press:  20 May 2015

F. B. Fahlbusch ,
A. Hartner ,
C. Menendez-Castro ,
S. C. Nögel ,
I. Marek ,
M. W. Beckmann ,
E. Schleussner ,
M. Ruebner ,
H. Huebner  and
H.-G. Dörr
...Show all authors
F. B. Fahlbusch*
Affiliation:
Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany
A. Hartner
Affiliation:
Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany
C. Menendez-Castro
Affiliation:
Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany
S. C. Nögel
Affiliation:
Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany
I. Marek
Affiliation:
Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany
M. W. Beckmann
Affiliation:
Department of Gynecology and Obstetrics, University of Erlangen-Nürnberg, Erlangen, Germany
E. Schleussner
Affiliation:
Department of Gynecology and Obstetrics, University of Jena, Jena, Germany
M. Ruebner
Affiliation:
Department of Gynecology and Obstetrics, University of Erlangen-Nürnberg, Erlangen, Germany
H. Huebner
Affiliation:
Department of Gynecology and Obstetrics, University of Erlangen-Nürnberg, Erlangen, Germany
H.-G. Dörr
Affiliation:
Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany
R. L. Schild
Affiliation:
Department of Obstetrics & Gynecology, Diakonische Dienste Hannover, Hannover, Germany
J. Dötsch
Affiliation:
Childrens’ and Adolescents’ Hospital, University of Cologne, Cologne, Germany
W. Rascher
Affiliation:
Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany
*
*Address for correspondence: F. B. Fahlbusch, MD, Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Loschgestr. 15, Erlangen 91054, Germany. (Email fabian.fahlbusch@uk-erlangen.de)
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Abstract

Idiopathic intrauterine growth restriction (IUGR) is a result of impaired placental nutrient supply. Newborns with IUGR exhibiting postnatal catch-up growth are of higher risk for cardiovascular and metabolic co-morbidities in adult life. Mammalian target of rapamycin (mTOR) was recently shown to function as a placental nutrient sensor. Thus, we determined possible correlations of members of the placental mTOR signaling cascade with auxologic parameters of postnatal growth. The protein expression and activity of mTOR-pathway signaling components, Akt, AMP-activated protein kinase α, mTOR, p70S6kinase1 and insulin receptor substrate-1 were analysed via western blotting in IUGR v. matched appropriate-for-gestational age (AGA) placentas. Moreover, mTOR was immunohistochemically stained in placental sections. Data from western blot analyses were correlated with retrospective auxological follow-up data at 1 year of age. We found significant catch-up growth in the 1st year of life in the IUGR group. MTOR and its activated form are immunohistochemically detected in multiple placental compartments. We identified correlations of placental mTOR-pathway signaling components to auxological data at birth and at 1 year of life in IUGR. Analysis of the protein expression and phosphorylation level of mTOR-pathway components in IUGR and AGA placentas postpartum, however, did not reveal pathognomonic changes. Our findings suggest that the level of activated mTOR correlates with early catch-up growth following IUGR. However, the complexity of signals converging at the mTOR nexus and its cellular distribution pattern seem to limit its potential as biomarker in this setting.

Keywords

IUGRmTORplacentapostnatal development
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 6 , Supplement 4 , August 2015 , pp. 317 - 326
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Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2015 

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References

1. Jansson, N, Pettersson, J, Haafiz, A, et al. Down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet. J Physiol. 2006; 576(Pt 3), 935–946.Google ScholarPubMed
2. Jansson, T, Powell, TL. IFPA 2005 Award in Placentology Lecture. Human placental transport in altered fetal growth: does the placenta function as a nutrient sensor? – a review. Placenta. 2006; 27(Suppl. A), S91–S97.Google Scholar
3. Roos, S, Lagerlof, O, Wennergren, M, Powell, TL, Jansson, T. Regulation of amino acid transporters by glucose and growth factors in cultured primary human trophoblast cells is mediated by mTOR signaling. Am J Physiol Cell Physiol. 2009; 297, C723–C731.CrossRefGoogle ScholarPubMed
4. Roos, S, Powell, TL, Jansson, T. Placental mTOR links maternal nutrient availability to fetal growth. Biochem Soc Trans. 2009; 37(Pt 1), 295–298.Google Scholar
5. Brodsky, D, Christou, H. Current concepts in intrauterine growth restriction. J Intensive Care Med. 2004; 19, 307–319.CrossRefGoogle ScholarPubMed
6. Barker, DJ. The Wellcome Foundation Lecture, 1994. The fetal origins of adult disease. Proc Biol Sci. 1995; 262, 37–43.Google Scholar
7. Curhan, GC, Willett, WC, Rimm, EB, et al. Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation. 1996; 94, 3246–3250.CrossRefGoogle ScholarPubMed
8. Ong, KK, Ahmed, ML, Emmett, PM, Preece, MA, Dunger, DB. Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ. 2000; 320, 967–971.Google Scholar
9. Metcalfe, NB, Monaghan, P. Compensation for a bad start: grow now, pay later? Trends Ecol Evol. 2001; 16, 254–260.CrossRefGoogle ScholarPubMed
10. Boekelheide, K, Blumberg, B, Chapin, RE, et al. Predicting later-life outcomes of early-life exposures. Environ Health Perspect. 2012; 120, 1353–1361.CrossRefGoogle ScholarPubMed
11. Dulloo, AG. Regulation of fat storage via suppressed thermogenesis: a thrifty phenotype that predisposes individuals with catch-up growth to insulin resistance and obesity. Hormone Res. 2006; 65(Suppl. 3), 90–97.Google Scholar
12. Dulloo, AG, Jacquet, J, Seydoux, J, Montani, JP. The thrifty ‘catch-up fat’ phenotype: its impact on insulin sensitivity during growth trajectories to obesity and metabolic syndrome. Int J Obes. 2006; 30(Suppl. 4), S23–S35.Google Scholar
13. Roos, S, Kanai, Y, Prasad, PD, Powell, TL, Jansson, T. Regulation of placental amino acid transporter activity by mammalian target of rapamycin. Am J Physiol Cell Physiol. 2009; 296, C142–C150.Google Scholar
14. Busch, S, Renaud, SJ, Schleussner, E, Graham, CH, Markert, UR. mTOR mediates human trophoblast invasion through regulation of matrix-remodeling enzymes and is associated with serine phosphorylation of STAT3. Exp Cell Res. 2009; 315, 1724–1733.CrossRefGoogle ScholarPubMed
15. Harrington, LS, Findlay, GM, Lamb, RF. Restraining PI3K: mTOR signalling goes back to the membrane. Trends Biochem Sci. 2005; 30, 35–42.CrossRefGoogle ScholarPubMed
16. Um, SH, Frigerio, F, Watanabe, M, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature. 2004; 431, 200–205.Google Scholar
17. Bouzakri, K, Roques, M, Gual, P, et al. Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes. 2003; 52, 1319–1325.CrossRefGoogle ScholarPubMed
18. LeRoith, D, Werner, H, Beitner-Johnson, D, Roberts, CT Jr. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev. 1995; 16, 143–163.Google Scholar
19. De Blasio, MJ, Gatford, KL, McMillen, IC, Robinson, JS, Owens, JA. Placental restriction of fetal growth increases insulin action, growth, and adiposity in the young lamb. Endocrinology. 2007; 148, 1350–1358.CrossRefGoogle ScholarPubMed
20. De Blasio, MJ, Gatford, KL, Harland, ML, Robinson, JS, Owens, JA. Placental restriction reduces insulin sensitivity and expression of insulin signaling and glucose transporter genes in skeletal muscle, but not liver, in young sheep. Endocrinology. 2012; 153, 2142–2151.Google Scholar
21. Hay, N, Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 2004; 18, 1926–1945.Google Scholar
22. Skeen, JE, Bhaskar, PT, Chen, CC, et al. Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. Cancer Cell. 2006; 10, 269–280.Google Scholar
23. Yang, ZZ, Tschopp, O, Hemmings-Mieszczak, M, et al. Protein kinase B alpha/Akt1 regulates placental development and fetal growth. J Biol Chem. 2003; 278, 32124–32131.CrossRefGoogle ScholarPubMed
24. Ma, Y, Zhu, MJ, Uthlaut, AB, et al. Upregulation of growth signaling and nutrient transporters in cotyledons of early to mid-gestational nutrient restricted ewes. Placenta. 2011; 32, 255–263.CrossRefGoogle ScholarPubMed
25. Hardie, DG. The AMP-activated protein kinase pathway – new players upstream and downstream. J Cell Sci. 2004; 117(Pt 23), 5479–5487.CrossRefGoogle ScholarPubMed
26. Kovacic, S, Soltys, CL, Barr, AJ, et al. Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem. 2003; 278, 39422–39427.CrossRefGoogle ScholarPubMed
27. Minokoshi, Y, Alquier, T, Furukawa, N, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004; 428, 569–574.Google Scholar
28. Gudmundsson, S, Korszun, P, Olofsson, P, Dubiel, M. New score indicating placental vascular resistance. Acta obstetricia et gynecologica Scandinavica. 2003; 82, 807–812.Google Scholar
29. Fahlbusch, FB, Dawood, Y, Hartner, A, et al. Cullin 7 and Fbxw 8 expression in trophoblastic cells is regulated via oxygen tension: implications for intrauterine growth restriction? J Matern Fetal Neonatal Med. 2012; 25, 2209–2215.Google Scholar
30. Ghidini, A. Idiopathic fetal growth restriction: a pathophysiologic approach. Obstet Gynecol Survey. 1996; 51, 376–382.Google Scholar
31. Voigt, M, Schneider, KT, Jahrig, K. Analysis of a 1992 birth sample in Germany. 1: New percentile values of the body weight of newborn infants. Geburtshilfe Und Frauenheilkunde. 1996; 56, 550–558.Google Scholar
32. Kromeyer-Hauschild, K, Wabitsch, M, Kunze, D, et al. Percentiles for the body mass index for the child and young adult under consulting different German samples. Monatsschr Kinderheilkd. 2001; 149, 807–818.Google Scholar
33. Hartner, A, Porst, M, Gauer, S, et al. Glomerular osteopontin expression and macrophage infiltration in glomerulosclerosis of DOCA-salt rats. Am J Kidney Dis. 2001; 38, 153–164.Google Scholar
34. Sarbassov, DD, Guertin, DA, Ali, SM, Sabatini, DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005; 307, 1098–1101.CrossRefGoogle ScholarPubMed
35. Steinberg, TH. Protein gel staining methods: an introduction and overview. Methods Enzymol. 2009; 463, 541–563.CrossRefGoogle ScholarPubMed
36. Karlberg, J, Albertsson-Wikland, K. Growth in full-term small-for-gestational-age infants: from birth to final height. Pediatr Res. 1995; 38, 733–739.Google Scholar
37. Karlberg, JP, Albertsson-Wikland, K, Kwan, EY, Lam, BC, Low, LC. The timing of early postnatal catch-up growth in normal, full-term infants born short for gestational age. Hormone Res. 1997; 48(Suppl. 1), 17–24.CrossRefGoogle ScholarPubMed
38. Chatelain, P. Children born with intra-uterine growth retardation (IUGR) or small for gestational age (SGA): long term growth and metabolic consequences. Endocr Regul. 2000; 34, 33–36.Google Scholar
39. Victora, CG, Barros, FC, Horta, BL, Martorell, R. Short-term benefits of catch-up growth for small-for-gestational-age infants. Int J Epidemiol. 2001; 30, 1325–1330.Google Scholar
40. Frisk, V, Amsel, R, Whyte, HE. The importance of head growth patterns in predicting the cognitive abilities and literacy skills of small-for-gestational-age children. Dev Neuropsychol. 2002; 22, 565–593.Google Scholar
41. Rogers, I, Group, E-BS. The influence of birthweight and intrauterine environment on adiposity and fat distribution in later life. Int J Obes Relat Metab Disord. 2003; 27, 755–777.Google Scholar
42. Eriksson, JG, Forsen, T, Tuomilehto, J, et al. Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ. 1999; 318, 427–431.Google Scholar
43. Forsen, T, Eriksson, J, Qiao, Q, et al. Short stature and coronary heart disease: a 35-year follow-up of the finnish cohorts of the seven countries study. J Intern Med. 2000; 248, 326–332.Google Scholar
44. Street, ME, Viani, I, Ziveri, MA, et al. Impairment of insulin receptor signal transduction in placentas of intra-uterine growth-restricted newborns and its relationship with fetal growth. Eur J Endocrinol. 2011; 164, 45–52.CrossRefGoogle ScholarPubMed
45. Morgensztern, D, McLeod, HL. PI3K/Akt/mTOR pathway as a target for cancer therapy. AntiCancer Drugs. 2005; 16, 797–803.CrossRefGoogle ScholarPubMed
46. Roos, S, Jansson, N, Palmberg, I, et al. Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth. J Physiol. 2007; 582(Pt 1), 449–459.Google Scholar
47. Soliman, GA. The mammalian target of rapamycin signaling network and gene regulation. Curr Opin Lipidol. 2005; 16, 317–323.Google Scholar
48. Laviola, L, Perrini, S, Belsanti, G, et al. Intrauterine growth restriction in humans is associated with abnormalities in placental insulin-like growth factor signaling. Endocrinology. 2005; 146, 1498–1505.CrossRefGoogle ScholarPubMed
49. Rosario, FJ, Jansson, N, Kanai, Y, et al. Maternal protein restriction in the rat inhibits placental insulin, mTOR, and STAT3 signaling and down-regulates placental amino acid transporters. Endocrinology. 2011; 152, 1119–1129.CrossRefGoogle ScholarPubMed
50. Laplante, M, Sabatini, DM. mTOR signaling in growth control and disease. Cell. 2012; 149, 274–293.Google Scholar
51. Kavitha, JV, Rosario, FJ, Nijland, MJ, et al. Down-regulation of placental mTOR, insulin/IGF-I signaling, and nutrient transporters in response to maternal nutrient restriction in the baboon. FASEB J. 2014; 28, 1294–1305.CrossRefGoogle ScholarPubMed
52. Lager, S, Aye, IL, Gaccioli, F, et al. Labor inhibits placental mechanistic target of rapamycin complex 1 signaling. Placenta. 2014; 35, 1007–1012.Google Scholar
53. Hardwick, JS, Kuruvilla, FG, Tong, JK, Shamji, AF, Schreiber, SL. Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc Natl Acad Sci U S A. 1999; 96, 14866–14870.CrossRefGoogle ScholarPubMed
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