Abstract
Uteroplacental insufficiency alters the anabolic metabolism of the fetus, resulting in intrauterine growth retardation (IUGR). The metabolic and physiologic factors that cause IUGR have long standing consequences after birth. Postnatal growth and glucose metabolism are altered in the IUGR infant. Skeletal muscle is an important component of growth and metabolizes up to 70% of i.v. glucose. The ability of skeletal muscle to metabolize glucose is affected by ATP availability. We hypothesized that gene expression and function of proteins involved in mitochondrial ATP production and distribution would be altered in juvenile IUGR muscle. To test this hypothesis, we used a model of IUGR, induced by bilateral uterine artery ligation in the pregnant rat, that mimics uteroplacental insufficiency in the human. RT-PCR was used to measure the mRNA levels of three important mitochondrial proteins; NADH-ubiquinone-oxireductase subunit 4L(ND-4L), subunit C of the F1F0-ATP synthase (SUC), and adenine nucleotide translocator 1(ANT1) in IUGR and control rats in fetal and juvenile life. In the fetus, mRNA levels of all three proteins were significantly increased in IUGR skeletal muscle. In contrast, in juvenile animals, mRNA levels of all three proteins were significantly decreased. mRNA levels of other metabolically important proteins, glucose-6-phosphate dehydrogenase and carnitine-palmitoyl-transferase II, were not significantly altered in IUGR juvenile animals. To assess if decreased gene expression is associated with altered mitochondrial function, we measured the mitochondrial NAD+/NADH ratio in d 21 juvenile control and IUGR muscle. At d 21, decreased gene expression if ND-4L, SUC, and ANT1 is associated with a decreased mitochondrial NAD+/NADH ratio. The results of our study suggest that the metabolic alterations associated with uteroplacental insufficiency in the rat result in altered fetal and postnatal muscle mitochondrial mRNA expression as well as altered postnatal mitochondrial function.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- ANT1:
-
adenine-nucleotide translocator-1
- CPTII:
-
carnitine-palmitoyl-transferase II
- G6PD:
-
glucose-6-phosphate dehydrogenase
- IUGR:
-
intrauterine growth retardation
- ND-4L:
-
NADH-ubiquinone oxireductase subunit 4L
- RT:
-
reverse transcriptase
- SUC:
-
subunit C of the F1F0-ATPase
References
Ogata ES, Bussey ME, Finley S 1985 Altered gas exchange, limited glucose and branched chain amino acids and hypoinsulinism retard fetal growth in the rat. Metabolism 35: 970–977.
Ogata ES, Swanson SL, Collins JW, Finley SL 1990 Intrauterine growth retardation: altered hepatic energy and redox states in the fetal rat. Pediatr Res 27: 56–63.
Ogata ES, Bussey ME, LaBarbera A, Finley S 1985 Altered growth, hypoglycemia, hypoalaninemia, and ketonemia in the young rat: postanatal consequences of intrauterine growth retardation. Pediatr Res 19: 32–37.
Cetin I, Marconi AM, Bozzetti P, Serini LP, Corbetta C, Pardi G, Battaglia FC 1988 Umbilical amino acid concentrations in appropriate and small for gestational age infants: a biochemical difference present in utero. Am J Obstet Gynecol 158: 120–126.
Greenwald P 1963 Chronic fetal distress and placental insufficiency. Biol Neonate 5: 215–219.
Walther FJ 1988 Growth and development of term disproportionate small for gestational age infants at age 7 years. Early Hum Dev 18: 1–11.
Villar J, Smeriglio V, Martorell R, Browh CH, Klein RE 1984 Heterogeneous growth and mental development of intrauterine growth retarded infants during the first 3 years of life. Pediatrics 74: 783–791.
Vohr BR, OH W 1983 Growth and development in preterm infants small for gestational age. J Pediatr 103: 941–945.
Barros FC, Huttly SRA, Vitora CG, Kirkwood BR, Vaughan JP 1992 Comparison of the causes and consequences of prematurity and intrauterine growth retardation: a longitudinal study in southern brazil. Pediatrics 90: 238–244.
Sinclair JC, Silverman WA 1966 Intrauterine growth in active tissue mass of the human fetus with particular reference to the undergrown baby. Pediatrics 38: 48–62.
Chessex P, Reichman B, Verellen G, Putet G, Smith JM, Heim T, Swyer PR 1984 Metabolic consequences of intrauterine growth retardation in very low birthweight infants. Pediatr Res 18: 709–713.
Davies PW, Clough H, Bishop NJ, Lucas A, Cole JJ, Cole TJ 1996 Total energy expenditure in small for gestational age infants. Arch Dis Child 74:F208–F210.
Hill JR, Robinson DC 1968 Oxygen consumption in normally growth, small-for-dates, and large-for-dates new born infants. J Physiol 199: 685–703.
Bhakoo NN, Scopes JW 1974 Minimal rates of oxygen consumption in small-for-dates babies during the first week of life. Arch Dis Child 49: 583–585.
Lueder FL, Ogata ES 1990 Selective ligation of uterine artery branches accelerates fetal growth in the rat. Pediatr Res 24: 384–390.
Bussey ME, Finley SL, LaBarbera A, Ogata ES 1985 Hypoglycemia in the newborn growth retarded rat: delayed phosphoenol pryuvate carboxykinase induction despite increased glucagon availability. Pediatr Res 24: 384–390.
Cuezva JM, Fernandez E, Valcarce C, Medina JM 1983 The role of ATP/ADP ratio in the control of hepatic gluconeogenesis during the early neonatal period. Biochim Biophys Acta 759: 292–295.
Lynch RM, Carrington W, Fogarty KE, Fay FS 1996 Metabolic modulation of hexokinase in living smooth muscle cells. Am J Physiol 270:C488–C499.
Lee CP, GU Q, Xiong Y, Mitchell RA, Ernster L 1996 Mitochondrial P/O ratios consistently exceed 1:5 with succinate and 2.5 with NAD-linked substrates. FASEB J 10: 345–350.
Lane RH, Flozak AS, Ogata ES, Bell GI, Simmons RA 1996 Altered hepatic gene expression of enzymes involved in energy metabolism in the growth-retarded fetal rat. Pediatr Res 39: 390–394.
Simmons RA, Flozak AS, Ogata ES 1994 GLUT1 gene expression in growth retarded juvenile rats. Pediatr Res 35: 207A
Lane RH, Flozak AS, Simmons RA 1996 Measurement of GLUT mRNA in liver of fetal and neonatal rats using a novel method of quantitative polymerase chain reaction Biochem Mol M. ed 59: 192–199.
Fillingame RH 1992 Subunit C of F1F0-ATP synthase: structure and role in transmembrane energy transduction. Biochim Biophys Acta 1101: 241–243.
Houstek J, Andersson U, Tvrdik P, Nedergaard J, Cannon B 1995 The expression of subunit C correlates with and thus may limit the biosynthesis of the mitochondrial F1F0-ATP synthase in brown adipose tissue. J Biol Chem 270: 7689–7694.
Shinohara Y, Kamida M, Yamazaki N, Tereda H 1993 Isolation and Characterization of cDNA clones and a genomic clone encoding mitochondrial adenine nucleotide translocator. Biochim Biophys Acta 1152: 192–196.
Devin A, Guerin B, Rigoulet M 1995 Dependence of flux size and efficiency of oxidative phosphorylation on external osmolarity in isolated rat liver mitochondria: role of adenine nucleotide carrier. Biochim Biophys Acta 1273: 13–20.
Williamson DH, Lund P, Krebs HA 1967 The redox state of free nicotinamideadenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem J 103: 514–527.
Williams JR, Cooper RH 1980 Regulation of the Citric Acid Cycle in Mammalian Systems. FEBS Lett 117S:K73–K85.
Salway JG 1994 Metabolism at a Glance. Blackwell Scientific Publications, Cambridge,. MA 74: 75
Simmons RA, Gounis AS, Bangalore SA, Ogata ES 1992 Intratuterine growth retardation: fetal glucose transport is diminished in lung but spared in brain. Pediatr Res 31: 59–63.
Chomczynski P, Sacchi N 1987 Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159.
Gadaleta G, Pepe G, DeCandia G, Quagliariello C, Sbisa E, Saccone C 1989 The complete nucleotide sequence of the rattus norvegicus mitochondrial genome: cryptic signals revealed by comparative analysis between vertebrates. J Mol Evol 28: 497–516.
Higuti T, Kurowa K, Kawamura Y, Morimoto K, Tsujita H 1993 Molecular cloning and sequence of cDNA's for the import precursors of oligomycin sensitivity conferring protein. ATPase inhibitor protein, and subunit c of H+-ATP synthase of rat mitochondria. Biochim Biophys Acta 1172: 311–314.
Ho YS, Howard AJ, Crapo JD 1988 Cloning and sequence of a cDNA encoding rat glucose-6-phosphate dehydrogenase. Nucleic Acids Res 16: 7746
Woeltje KF, Esser V, Weis BC, Sen A, Cox WF, McPhaul MJ, Slaughter CA, Foster DW, McGarry JD 1990 Cloning, sequencing, and expression of a cDNA encoding rat liver mitochondrial carnitine palmitoyltransferase II. J Biol Chem 265: 10720–10725.
Kuo CH, Yamagata K, Moyzis RK, Bitensky MW, Miki N 1986 Multiple opsin mRNA species in bovine retina. Mol Brain Res 1: 251–260.
Ballard FJ 1970 Adenine nuclotides and adenylate kinase equilibrium in livers of foetal and newborn rats. Biochem J 117: 231–238.
Zar JH 1984 Biostatistical Analysis. Prentice Hall, Englewood Cliffs, NJ
Walker JE 1992 The NADH: ubiquinone oxireductase(complex I) of respiratory chains. Q Rev Biophys 25: 253–324.
Luciakova K, Li R, Nelson BD 1992 Differential regulation of the transcript levels of some nuclear-encoded and mitochondrial encoded respiratory chain components in response to growth activation. Eur J Biochem 207: 253–257.
Shonfeld P, Schild L, Bohnensack R 1996 Expression of the ADP/ATP carrier and expansion of the mitochondrial (ATP + ADP) pool contribute to postnatal maturation of the rat heart. Eur J Biochem 241: 895–900.
Tager JM, Wanders RJA, Groen AK, Kunz W, Bohnensack R, Kuster U, Letko G, Bohme G, Duszynski J, Wojtczak 1983 Control of Mitochondrial Respiration. FEBS Lett 151: 1–9.
Holzhutter HG, Henke W, Dubiel W, Gerber G 1985 A mathematical model to study short term regulation of mitochondrial energy transduction. Biochim Biophys Acta 810: 252–268.
Hale DE, Williamson JR 1984 Developmental changes in the adenine nucleotide translocase in the guinea pig. J Biol Chem 259: 8737–8742.
Heddi A, Lestienne P, Wallace DC, Stepien G 1993 Mitochondrial DNA expression in mitochondrial myopathies and coordinated expression of nuclear genes involved in ATP production. J Biol Chem 268: 12156–12163.
Heddi A, Faure-Vigny H, Wallace DC, Stepien G 1996 Coordinated expression of nuclear and mitochondrial genes involved in energy production in carinoma and oncocytoma. Biochim Biophys Acta 1316: 203–209.
Ozolins TR, Hales BF 1997 Oxidative stress regulates the expression and activity of transcription factor activator protein-1 in rat conceptus. J Pharmacol Exp Ther 280: 1085–1093.
Lin TN, Te J, Huang HC, Chi SI, Hsu CY 1997 Prolongation and enhancement of postischemic c-fos expression after fasting. Stroke 28: 412–418.
Garry DJ, Bassel-Duby RS, Richardson JA, Grayson J, Neufer PD, Williams RS 1996 Postnatal development and plasticity of specialized muscle fiber characteristics in the hindlimb. Dev Genet 19: 146–156.
Jackman MR, Willis WT 1996 Characteristics of mitochondria isolated from type I and type IIb skeletal muscle. Am J Physiol 270:C673–C678.
Simoneau JA, Bouchard C 1989 Human variation in skeletal muscle fiber type proportion and enzyme activities Am J P. hysiol 257:E567–E572.
Hofman PL, Cutfield WS, Robinson EM, Bergman RN, Menon RK, Sperling MA, Gluckman PD 1997 Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab 82: 402–406.
Yajnik CS, Fall CH, Vaidya U, Pandit AN, Bavdekar A, Bhat DS, Osmond C, Hales CN, Barker DJ 1995 Fetal growth and glucose and insulin metabolism in four year old Indian children. Diabet Med 12: 330–336.
Law CM, Gordon GS, Shiell AW, Barker DJP, Hales CN 1995 Thinness at birth and glucose tolerance in seven year old children. Diabet Med 12: 24–29.
Robinson S, Walton RJ, Clark PM, Barker DJP, Hales CN, Osmond C 1992 The relation of fetal growth to plasma glucose in young men. Diabetologia 35: 444–446.
Philpps K, Barker DJP, Hales CN, Fall CHD, Osmond C, Clark PMS 1993 Fetal growth and impaired glucose tolerance in men and women. Diabetologia 36: 225–228.
Barker DJP, Hales CN, Fall CHD, Osmond C, Phipps K, Clark 1993 Type 2 (non-insulin-dependent) diabetes mellitus, hypertension, and hyperlipidaemia syndrome X): relation to reduced fetal growth. Diabetologia 36: 62–67.
Valez R, Athens MA, Thompson GH, Bradshaw BS, Stern MP 1994 Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia 37: 624–631.
Thompson CH, Sanderson AL, Sandeman D, Stein C, Borthwick A, Radda GK, Phillips DI 1997 Fetal growth and insulin resistance in adult life: role of skeletal muscle. Clin Sci 92: 291–296.
Sacks DB, McDonald JM 1995 The pathogenesis of type II diabetes mellitus. Am J Clin Pathol 105: 149–156.
Leger J, Levy-Marchal C, Bloch J, Pinet A, Chevenne D, Porquet D, Collin D, Czernichow P 1997 Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study. BMJ 315: 341–347.
Nolan JJ, Ludvik B, Baloga J, Reichart D, Olefsky JM 1997 Mechanisms of the kinetic defect in insulin action in obesity and NIDDM. Diabetes 46: 994–1000.
Lynch RM, Carrington W, Fogarty KE, Fay FS 1996 Metabolic modulation of hexokinase in living smooth muscle cells. Am J Physiol 270:C488–C499.
Goncharova Niu, Zalenina EV 1991 The effect of insulin on the catalytic efficacy of rat skeletal muscle hexokinase isoenzyme II. Biokhimiia 56: 913–922.
Simoneau JA, Colberg SR, Thaete FL, Kelley DE 1995 Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women. FASEB J 9: 273–289.
Acknowledgements
The authors thank Dr. Graeme Bell, Dr. Edward Ogata, and Dr. Sherin Devaskar for their support and guidance.
Author information
Authors and Affiliations
Additional information
Supported by National Institute of Child Health and Human Development Grant P30HD-28836-05.
Rights and permissions
About this article
Cite this article
Lane, R., Chandorkar, A., Flozak, A. et al. Intrauterine Growth Retardation Alters Mitochondrial Gene Expression and Function in Fetal and Juvenile Rat Skeletal Muscle. Pediatr Res 43, 563–570 (1998). https://doi.org/10.1203/00006450-199805000-00001
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-199805000-00001
This article is cited by
-
Intrauterine growth restriction impairs right ventricular response to hypoxia in adult male rats
Pediatric Research (2016)
-
Growth restriction before or after birth reduces nephron number and increases blood pressure in male rats
Kidney International (2008)
-
Mitochondrial DNA Depletion in Small‐ and Large‐for‐Gestational‐Age Newborns
Obesity (2006)
