Aurélie Bourdon1, Patricia Parnet1, Christel Nowak2, Nhat-Thang Tran1, Norbert Winer2, Dominique Darmaun3. 1. National Institute of Agricultural Research (INRA), Joint Research Unit (UMR 1280), Physiology of Nutritional Adaptations, University of Nantes, Institute for Diseases of the Digestive System (IMAD), and Western Human Nutrition Research Center (CRNH), Nantes, France; 2. National Institute of Agricultural Research (INRA), Joint Research Unit (UMR 1280), Physiology of Nutritional Adaptations, University of Nantes, Institute for Diseases of the Digestive System (IMAD), and Western Human Nutrition Research Center (CRNH), Nantes, France; Department of Gynecology and Obstetrics, University Medical Center of Nantes, Nantes, France; and. 3. National Institute of Agricultural Research (INRA), Joint Research Unit (UMR 1280), Physiology of Nutritional Adaptations, University of Nantes, Institute for Diseases of the Digestive System (IMAD), and Western Human Nutrition Research Center (CRNH), Nantes, France; Nutrition Support Team, IMAD, University Medical Center of Nantes, Nantes, France ddarmaun@chu-nantes.fr.
Abstract
BACKGROUND: Intrauterine growth restriction (IUGR) results from either maternal undernutrition or impaired placental blood flow, exposing offspring to increased perinatal mortality and a higher risk of metabolic syndrome and cardiovascular disease during adulthood. l-Citrulline is a precursor of l-arginine and nitric oxide (NO), which regulates placental blood flow. Moreover, l-citrulline stimulates protein synthesis in other models of undernutrition. OBJECTIVE: The aim of the study was to determine whether l-citrulline supplementation would enhance fetal growth in a model of IUGR induced by maternal dietary protein restriction. METHODS: Pregnant rats were fed either a control (20% protein) or a low-protein (LP; 4% protein) diet. LP dams were randomly allocated to drink tap water either as such or supplemented with l-citrulline (2 g · kg(-1) · d(-1)), an isonitrogenous amount of l-arginine, or nonessential l-amino acids (NEAAs). On day 21 of gestation, dams received a 2-h infusion of l-[1-(13)C]-valine until fetuses were extracted by cesarean delivery. Isotope enrichments were measured in free amino acids and fetal muscle, liver, and placenta protein by GC-mass spectrometry. RESULTS: Fetal weight was ∼29% lower in the LP group (3.82 ± 0.06 g) than in the control group (5.41 ± 0.10 g) (P < 0.001). Regardless of supplementation, fetal weight remained below that of control fetuses. Yet, compared with the LP group, l-citrulline and l-arginine equally increased fetal weight to 4.15 ± 0.08 g (P < 0.05) and 4.13 ± 0.1 g (P < 0.05 compared with LP), respectively, whereas NEAA did not (4.05 ± 0.05 g; P = 0.07). Fetal muscle protein fractional synthesis rate was 35% lower in the LP fetuses (41% ± 11%/d) than in the control (61% ± 13%/d) fetuses (P < 0.001) and was normalized by l-citrulline (56% ± 4%/d; P < 0.05 compared with LP, NS compared with control) and not by other supplements. Urinary nitrite and nitrate excretion was lower in the LP group (6.4 ± 0.8 μmol/d) than in the control group (17.9 ± 1.1 μmol/d; P < 0.001) and increased in response to l-citrulline or l-arginine (12.1 ± 2.2 and 10.6 ± 0.9 μmol/d; P < 0.05), whereas they did not in the LP + NEAA group. CONCLUSION: l-Citrulline increases fetal growth in a model of IUGR, and the effect may be mediated by enhanced fetal muscle protein synthesis and/or increased NO production.
BACKGROUND: Intrauterine growth restriction (IUGR) results from either maternal undernutrition or impaired placental blood flow, exposing offspring to increased perinatal mortality and a higher risk of metabolic syndrome and cardiovascular disease during adulthood. l-Citrulline is a precursor of l-arginine and nitric oxide (NO), which regulates placental blood flow. Moreover, l-citrulline stimulates protein synthesis in other models of undernutrition. OBJECTIVE: The aim of the study was to determine whether l-citrulline supplementation would enhance fetal growth in a model of IUGR induced by maternal dietary protein restriction. METHODS: Pregnant rats were fed either a control (20% protein) or a low-protein (LP; 4% protein) diet. LP dams were randomly allocated to drink tap water either as such or supplemented with l-citrulline (2 g · kg(-1) · d(-1)), an isonitrogenous amount of l-arginine, or nonessential l-amino acids (NEAAs). On day 21 of gestation, dams received a 2-h infusion of l-[1-(13)C]-valine until fetuses were extracted by cesarean delivery. Isotope enrichments were measured in free amino acids and fetal muscle, liver, and placenta protein by GC-mass spectrometry. RESULTS: Fetal weight was ∼29% lower in the LP group (3.82 ± 0.06 g) than in the control group (5.41 ± 0.10 g) (P < 0.001). Regardless of supplementation, fetal weight remained below that of control fetuses. Yet, compared with the LP group, l-citrulline and l-arginine equally increased fetal weight to 4.15 ± 0.08 g (P < 0.05) and 4.13 ± 0.1 g (P < 0.05 compared with LP), respectively, whereas NEAA did not (4.05 ± 0.05 g; P = 0.07). Fetal muscle protein fractional synthesis rate was 35% lower in the LP fetuses (41% ± 11%/d) than in the control (61% ± 13%/d) fetuses (P < 0.001) and was normalized by l-citrulline (56% ± 4%/d; P < 0.05 compared with LP, NS compared with control) and not by other supplements. Urinary nitrite and nitrate excretion was lower in the LP group (6.4 ± 0.8 μmol/d) than in the control group (17.9 ± 1.1 μmol/d; P < 0.001) and increased in response to l-citrulline or l-arginine (12.1 ± 2.2 and 10.6 ± 0.9 μmol/d; P < 0.05), whereas they did not in the LP + NEAA group. CONCLUSION:l-Citrulline increases fetal growth in a model of IUGR, and the effect may be mediated by enhanced fetal muscle protein synthesis and/or increased NO production.
Authors: Fieke Terstappen; Angela J C Tol; Hendrik Gremmels; Kimberley E Wever; Nina D Paauw; Jaap A Joles; Eline M van der Beek; A Titia Lely Journal: Nutrients Date: 2020-08-21 Impact factor: 5.717
Authors: Andrea M Weckman; Chloe R McDonald; Jo-Anna B Baxter; Wafaie W Fawzi; Andrea L Conroy; Kevin C Kain Journal: Adv Nutr Date: 2019-09-01 Impact factor: 8.701
Authors: Elizabeth Cottrell; Teresa Tropea; Laura Ormesher; Susan Greenwood; Mark Wareing; Edward Johnstone; Jenny Myers; Colin Sibley Journal: J Physiol Date: 2017-02-27 Impact factor: 5.182
Authors: Kris Genelyn Dimasuay; Elizabeth H Aitken; Fredrick Rosario; Madi Njie; Jocelyn Glazier; Stephen J Rogerson; Freya J I Fowkes; James G Beeson; Theresa Powell; Thomas Jansson; Philippe Boeuf Journal: BMC Med Date: 2017-01-03 Impact factor: 8.775
Authors: Jorge Y P Palencia; Alysson Saraiva; Márvio Lobão Teixeira Abreu; Marcio G Zangeronimo; Allan P Schinckel; Cesar Augusto Pospissil Garbossa Journal: PLoS One Date: 2018-12-20 Impact factor: 3.240