Skip to main content Accesibility Help

Maternal undernutrition around the time of conception and embryo number each impact on the abundance of key regulators of cardiac growth and metabolism in the fetal sheep heart

  • S. Lie (a1), S. M. Sim (a1), I. C. McMillen (a1), O. Williams-Wyss (a1) (a2), S. M. MacLaughlin (a1), D. O. Kleemann (a3), S. K. Walker (a3), C. T. Roberts (a4) and J. L. Morrison (a1)...

Poor maternal nutrition before and during pregnancy is associated with an increased risk of cardiovascular disease in later life. To determine the impact of maternal undernutrition during the periconceptional (PCUN: −45 days to 6 days) and preimplantation (PIUN: 0–6 days) periods on cardiac growth and metabolism, we have quantified the mRNA and protein abundance of key regulators of cardiac growth and metabolism in the left ventricle of the sheep fetus in late gestation. The cardiac protein abundance of AMP-activated protein kinase (AMPK), phospho-acetyl CoA carboxykinase (ACC) and pyruvate dehydrogenase kinase-4 (PDK-4) were decreased, whereas ACC was increased in singletons in the PCUN and PIUN groups. In twins, however, cardiac ACC was decreased in the PCUN and PIUN groups, and carnitine palmitoyltransferase-1 (CPT-1) was increased in the PIUN group. In singletons, the cardiac abundance of insulin receptor β (IRβ) was decreased in the PCUN group, and phosphoinositide-dependent protein kinase-1 (PDPK-1) was decreased in the PCUN and PIUN groups. In twins, however, the cardiac abundance of IRβ and phospho-Akt substrate 160kDa (pAS160) were increased in the PIUN group. The cardiac abundance of insulin-like growth factor-2 receptor (IGF-2R), protein kinase C alpha (PKCα) and mammalian target of rapamycin (mTOR) were decreased in PCUN and PIUN singletons and extracellular-signal-regulated kinase (ERK) was also decreased in the PIUN singletons. In contrast, in twins, cardiac abundance of IGF-2R and PKCα were increased in the PCUN and PIUN groups, phospho-ribosomal protein S6 (pRPS6) was increased in the PCUN group, and ERK and eukaryotic initiation factor 4E (eIF4E) were also increased in the PIUN fetuses. In conclusion, maternal undernutrition limited to around the time of conception is sufficient to alter the abundance of key factors regulating cardiac growth and metabolism and this may increase the propensity for cardiovascular diseases in later life.

Corresponding author
*Address for correspondence: A/Prof. J. L. Morrison, Heart Foundation South Australian Cardiovascular Health Network Fellow, Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, GPO Box 2471, Adelaide, SA 5001, Australia. (Email
Hide All
1.Edwards, LJ, McMillen, IC. Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep. Am J Physiol Regul Integr Comp Physiol. 2002; 283, R669R679.
2.Kwong, WY, Wild, AE, Roberts, P, Willis, AC, Fleming, TP. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development. 2000; 127, 41954202.
3.Gardner, DS, Pearce, S, Dandrea, J, et al. Peri-implantation undernutrition programs blunted angiotensin II evoked baroreflex responses in young adult sheep. Hypertension. 2004; 43, 12901296.
4.MacLaughlin, SM, Walker, SK, Kleemann, DO, et al. Impact of periconceptional undernutrition on adrenal growth and adrenal insulin-like growth factor and steroidogenic enzyme expression in the sheep fetus during early pregnancy. Endocrinology. 2007; 148, 19111920.
5.Roseboom, T, de Rooij, S, Painter, R. The Dutch famine and its long-term consequences for adult health. Earl Hum Dev. 2006; 82, 485491.
6.Watkins, AJ, Wilkins, A, Cunningham, C, et al. Low protein diet fed exclusively during mouse oocyte maturation leads to behavioural and cardiovascular abnormalities in offspring. J Physiol. 2008; 586, 22312244.
7.Roseboom, TJ, van der Meulen, JH, Ravelli, AC, et al. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Twin Res. 2001; 4, 293298.
8.Roseboom, TJ, van der Meulen, JHP, Osmond, C, et al. Coronary heart disease after prenatal exposure to the Dutch famine, 1944–45. Heart. 2000; 84, 595598.
9.Roseboom, TJ, van der Meulen, JHP, Osmond, C, et al. Plasma lipid profiles in adults after prenatal exposure to the Dutch famine. Am J Clin Nutr. 2000; 72, 11011106.
10.Painter, RC, de Rooij, SR, Bossuyt, PM, et al. Early onset of coronary artery disease after prenatal exposure to the Dutch famine. Am J Clin Nutr. 2006; 84, 322327.
11.Levy, D, Garrison, RJ, Savage, DD, Kannel, WB, Castelli, WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990; 322, 15611566.
12.Mandavia, CH, Aroor, AR, DeMarco, VG, Sowers, JR. Molecular and metabolic mechanisms of cardiac dysfunction in diabetes. Life Sci. 2012; 92, 601608.
13.Brooks, G, Poolman, RA, Li, J-M. Arresting developments in the cardiac myocyte cell cycle: role of cyclin-dependent kinase inhibitors. Cardiovasc Res. 1998; 39, 301311.
14.Cohick, WS, Clemmons, DR. The insulin-like growth factors. Annu Rev Physiol. 1993; 55, 131153.
15.Sherr, CJ. G1 phase progression: cycling on cue. Cell. 1994; 79, 551555.
16.Sundgren, NC, Giraud, GD, Schultz, JM, et al. Extracellular signal-regulated kinase and phosphoinositol-3 kinase mediate IGF-1 induced proliferation of fetal sheep cardiomyocytes. Am J Physiol Regul Integr Comp Physiol. 2003; 285, R1481R1489.
17.Kornfeld, S. Structure and function of the mannose 6-phosphate/insulin like growth factor II receptors. Annu Rev Biochem. 1992; 61, 307330.
18.Chu, CH, Tzang, BS, Chen, LM, et al. IGF-II/mannose-6-phosphate receptor signaling induced cell hypertrophy and atrial natriuretic peptide/BNP expression via Galphaq interaction and protein kinase C-alpha/CaMKII activation in H9c2 cardiomyoblast cells. J Endocrinol. 2008; 197, 381390.
19.Wang, KCW, Brooks, DA, Thornburg, KL, Morrison, JL. Activation of IGF-2R stimulates cardiomyocyte hypertrophy in the late gestation sheep fetus. J Physiol. 2012; 590, 54255437.
20.Dietz, R, Haass, M, Kübler, W. Atrial natriuretic factor. Its possible role in hypertension and congestive heart failure. Am J Hypertens. 1989; 2, 29S33S.
21.Nishikimi, T, Maeda, N, Matsuoka, H. The role of natriuretic peptides in cardioprotection. Cardiovasc Res. 2006; 69, 318328.
22.Pause, A, Belsham, GJ, Gingras, A-C, et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature. 1994; 371, 762767.
23.Gingras, AC, Kennedy, SG, O'Leary, MA, Sonenberg, N, Hay, N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev. 1998; 12, 502513.
24.Kang, S, Chemaly, ER, Hajjar, RJ, Lebeche, D. Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. J Biol Chem. 2011; 286, 1846518473.
25.Brown, EJ, Beal, PA, Keith, CT, et al. Control of P70 S6 kinase by kinase-activity of FRAP in-vivo. Nature. 1995; 377, 441446.
26.Kawasome, H, Papst, P, Webb, S, et al. Targeted disruption of p70s6k defines its role in protein synthesis and rapamycin sensitivity. Proc Natl Acad Sci U S A. 1998; 95, 50335038.
27.Dong, F, Ford, SP, Fang, CX, et al. Maternal nutrient restriction during early to mid gestation up-regulates cardiac insulin-like growth factor (IGF) receptors associated with enlarged ventricular size in fetal sheep. Growth Horm IGF Res. 2005; 15, 291299.
28.Bertram, C, Khan, O, Ohri, S, et al. Transgenerational effects of prenatal nutrient restriction on cardiovascular and hypothalamic–pituitary–adrenal function. J Physiol. 2008; 586, 22172229.
29.Lopaschuk, GD, Jaswal, JS. Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J Cardiovasc Pharmacol. 2010; 56, 130140.
30.Hay, WWJ. Placental transport of nutrients to the fetus. Horm Res. 1994; 42, 215222.
31.Taniguchi, CM, Emanuelli, B, Kahn, CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006; 7, 8596.
32.Pineiro, R, Iglesias, MJ, Gallego, R, et al. Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Lett. 2005; 579, 51635169.
33.Yamauchi, T, Kamon, J, Ito, Y, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003; 423, 762769.
34.Park, SH, Gammon, SR, Knippers, JD, et al. Phosphorylation-activity relationships of AMPK and acetyl-CoA carboxylase in muscle. J Appl Physiol. 2002; 92, 24752482.
35.Lopaschuk, GD, Gamble, J. The 1993 Merck Frosst Award. Acetyl-CoA carboxylase: an important regulator of fatty acid oxidation in the heart. Can J Physiol Pharmacol. 1994; 72, 11011109.
36.McGarry, JD. The mitochondrial carnitine palmitoyltransferase system: its broadening role in fuel homoeostasis and new insights into its molecular features. Biochem Soc Trans. 1995; 23, 321324.
37.Kadowaki, T, Yamauchi, T. Adiponectin and adiponectin receptors. Endocr Rev. 2005; 26, 439451.
38.Wu, P, Sato, J, Zhao, Y, et al. Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart. Biochem J. 1998; 329, 197201.
39.Sugden, MC, Holness, MJ. Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases. Arch Physiol Biochem. 2006; 112, 139149.
40.Burrell, JH, Boyn, AM, Kumarasamy, V, et al. Growth and maturation of cardiac myocytes in fetal sheep in the second half of gestation. Anat Rec A Discov Mol Cell Evol Biol. 2003; 274A, 952961.
41.Jonker, SS, Zhang, L, Louey, S, et al. Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart. J Appl Physiol. 2007; 102, 11301142.
42.Watkins, AJ, Lucas, ES, Wilkins, A, Cagampang, FRA, Fleming, TP. Maternal periconceptional and gestational low protein diet affects mouse offspring growth, cardiovascular and adipose phenotype at 1 year of age. PLoS One. 2011; 6, e28745.
43.Roseboom, TJ, Painter, RC, van Abeelen, AFM, Veenendaal, MVE, de Rooij, SR. Hungry in the womb: what are the consequences? Lessons from the Dutch famine. Maturitas. 2011; 70, 141145.
44.Rutter, MK, Parise, H, Benjamin, EJ, et al. Impact of glucose intolerance and insulin resistance on cardiac structure and function. Circulation. 2003; 107, 448454.
45.Mora, A, Sakamoto, K, McManus, EJ, Alessi, DR. Role of the PDK1–PKB–GSK3 pathway in regulating glycogen synthase and glucose uptake in the heart. FEBS Lett. 2005; 579, 36323638.
46.Stride, N, Larsen, S, Treebak, JT, et al. 5′-AMP activated protein kinase is involved in the regulation of myocardial β-oxidative capacity in mice. Front Physiol. 2012; 3, article 33.
47.Turdi, S, Kandadi, MR, Zhao, J, et al. Deficiency in AMP-activated protein kinase exaggerates high fat diet-induced cardiac hypertrophy and contractile dysfunction. J Mol Cell Cardiol. 2011; 50, 712722.
48.Meurs, K, Lahmers, S, Keene, B, et al. A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher. Hum Genet. 2012; 131, 13191325.
49.Lopes, R, Solter, PF, Sisson, DD, Oyama, MA, Prosek, R. Characterization of canine mitochondrial protein expression in natural and induced forms of idiopathic dilated cardiomyopathy. Am J Vet Res. 2006; 67, 963970.
50.Samovski, D, Su, X, Xu, Y, Abumrad, NA, Stahl, PD. Insulin and AMPK regulate FA translocase/CD36 plasma membrane recruitment in cardiomyocytes via Rab GAP AS160 and Rab8a Rab GTPase. J Lipid Res. 2012; 53, 709717.
51.Ginion, A, Auquier, J, Benton, CR, et al. Inhibition of the mTOR/p70S6 K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake. Am J Physiol Heart Circ Physiol. 2011; 301, H469H477.
52.Waterland, RA, Michels, KB. Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr. 2007; 27, 363388.
53.Guay, C, Roggli, E, Nesca, V, Jacovetti, C, Regazzi, R. Diabetes mellitus, a microRNA-related disease? Transl Res. 2011; 157, 253264.
54.Rottiers, V, Najafi-Shoushtari, SH, Kristo, F, et al. MicroRNAs in metabolism and metabolic diseases. Cold Spring Harb Symp Quant Biol. 2011; 76, 225233.
55.Bartel, DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116, 281297.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Journal of Developmental Origins of Health and Disease
  • ISSN: 2040-1744
  • EISSN: 2040-1752
  • URL: /core/journals/journal-of-developmental-origins-of-health-and-disease
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed