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Dietary creatine supplementation during pregnancy: a study on the effects of creatine supplementation on creatine homeostasis and renal excretory function in spiny mice

Amino Acids volume 48, pages 1819–1830 (2016)Cite this article

Abstract

Recent evidence obtained from a rodent model of birth asphyxia shows that supplementation of the maternal diet with creatine during pregnancy protects the neonate from multi-organ damage. However, the effect of increasing creatine intake on creatine homeostasis and biosynthesis in females, particularly during pregnancy, is unknown. This study assessed the impact of creatine supplementation on creatine homeostasis, body composition, capacity for de novo creatine synthesis and renal excretory function in non-pregnant and pregnant spiny mice. Mid-gestation pregnant and virgin spiny mice were fed normal chow or chow supplemented with 5 % w/w creatine for 18 days. Weight gain, urinary creatine and electrolyte excretion were assessed during supplementation. At post mortem, body composition was assessed by Dual-energy X-ray absorptiometry, or tissues were collected to assess creatine content and mRNA expression of the creatine synthesising enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) and the creatine transporter (CrT1). Protein expression of AGAT and GAMT was also assessed by Western blot. Key findings of this study include no changes in body weight or composition with creatine supplementation; increased urinary creatine excretion in supplemented spiny mice, with increased sodium (P < 0.001) and chloride (P < 0.05) excretion in pregnant dams after 3 days of supplementation; lowered renal AGAT mRNA (P < 0.001) and protein (P < 0.001) expressions, and lowered CrT1 mRNA expression in the kidney (P < 0.01) and brain (P < 0.001). Creatine supplementation had minimal impact on creatine homeostasis in either non-pregnant or pregnant spiny mice. Increasing maternal dietary creatine consumption could be a useful treatment for birth asphyxia.

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References

  • Andres RH, Ducray ALD, Schlattner U, Wallimann T, Widmer HR (2008) Functions and effects of creatine in the central nervous system. Brain Res Bull 76:329–343

    CAS  Article  PubMed  Google Scholar 

  • Bender A, Auer DP, Merl T, Reilmann R, Saemann P, Yassouridis A, Bender J, Weindl A, Dose M, Gasser T (2005) Creatine supplementation lowers brain glutamate levels in Huntington’s disease. J Neurol 252:36–41

    CAS  Article  PubMed  Google Scholar 

  • Bohnhorst B, Geuting T, Peter CS, Dördelmann M, Wilken B, Poets CF (2004) Randomized, controlled trial of oral creatine supplementation (not effective) for apnea of prematurity. Pediatrics 113:e303–e307

    Article  PubMed  Google Scholar 

  • Braissant O, Henry H, Loup M, Eilers B, Bachmann C (2001) Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study. Mol Brain Res 86:193–201

    CAS  Article  PubMed  Google Scholar 

  • Cannata DJ, Ireland Z, Dickinson H, Snow RJ, Russell AP, West JM, Walker DW (2010) Maternal creatine supplementation from mid-pregnancy protects the diaphragm of the newborn spiny mouse from intrapartum hypoxia-induced damage. Pediatr Res 68:393–398

    CAS  PubMed  Google Scholar 

  • Dafnis E, Sabatini S (1992) The effect of pregnancy on renal function: physiology and pathophysiology. Am J Med Sci 303:184–205

    CAS  Article  PubMed  Google Scholar 

  • Dechent P, Pouwels P, Wilken B, Hanefeld F, Frahm J (1999) Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol-Regul Integr Comp Physiol 277:R698–R704

    CAS  Google Scholar 

  • Dickinson H and Walker D (2007) Managing a colony of spiny mice (Acomys cahirinus) for perinatal research. Australian and New Zealand Council for the Care of Animals in Research and Training (ANZCCART) News, 20(1):4–11

  • Dickinson H, Ireland ZJ, Larosa DA, O’Connell BA, Ellery S, Snow R, Walker DW (2013) Maternal dietary creatine supplementation does not alter the capacity for creatine synthesis in the newborn spiny mouse. Reprod Sci 20:1096–1102

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Dickinson H, Bain E, Wilkinson D, Middleton P, Crowther CA, Walker DW (2014a) Creatine for women in pregnancy for neuroprotection of the fetus. The Cochrane Library

  • Dickinson H, Ellery S, Ireland Z, Larosa D, Snow R, Walker DW (2014b) Creatine supplementation during pregnancy: summary of experimental studies suggesting a treatment to improve fetal and neonatal morbidity and reduce mortality in high-risk human pregnancy. BMC Pregn Childbirth 14:150

    Article  Google Scholar 

  • Ellery SJ, Ireland Z, Kett MM, Snow R, Walker DW, Dickinson H (2012) Creatine pretreatment prevents birth asphyxia-induced injury of the newborn spiny mouse kidney. Pediatr Res 73:201–208

    Article  PubMed  Google Scholar 

  • Ellery SJ, Larosa DA, Kett MM, Della Gatta PA, Snow RJ, Walker DW, Dickinson H (2015) Maternal creatine homeostasis is altered during gestation in the spiny mouse: is this a metabolic adaptation to pregnancy? BMC Preg Childbirth 15:92

    Article  Google Scholar 

  • Forsberg A, Nilsson E, Werneman J, Bergstrom J, Hultman E (1991) Muscle composition in relation to age and sex. Clin Sci (Lond) 81:249–256

    CAS  Article  Google Scholar 

  • Gualano B, Ferreira DC, Sapienza MT, Seguro AC, Lancha AH Jr (2010) Effect of short-term high-dose creatine supplementation on measured GFR in a young man with a single kidney. Am J Kidney Dis 55:e7–e9

    CAS  Article  PubMed  Google Scholar 

  • Guerrero ML, Beron J, Spindler B, Groscurth P, Wallimann T, Verrey F (1997) Metabolic support of Na+ pump in apically permeabilized A6 kidney cell epithelia: role of creatine kinase. Am J Physiol Cell Physiol 272:C697–C706

    CAS  Google Scholar 

  • Guthmiller P, van Pilsum J, Boen JR, McGuire DM (1994) Cloning and sequencing of rat kidney l-arginine: glycine amidinotransferase. Studies on the mechanism of regulation by growth hormone and creatine. J Biol Chem 269:17556

    CAS  PubMed  Google Scholar 

  • Hall JE (2010) Guyton and hall textbook of medical physiology: enhanced e-book, Elsevier Health Sciences

  • Hanna-El-daher L, Béard E, Henry H, Tenenbaum L, Braissant O (2015) Mild guanidinoacetate increase under partial guanidinoacetate methyltransferase deficiency strongly affects brain cell development. Neurobiol Dis 79:14–27

    CAS  Article  PubMed  Google Scholar 

  • Hultman E, Soderlund K, Timmons J, Cederblad G, Greenhaff P (1996) Muscle creatine loading in men. J Appl Physiol 81:232–237

    CAS  PubMed  Google Scholar 

  • Ireland Z, Dickinson H, Snow R, Walker D (2008) Maternal creatine: does it reach the fetus and improve survival after an acute hypoxic episode in the spiny mouse (Acomys cahirinus)? Am J Obstet Gynecol 198:431–436

    Article  PubMed  Google Scholar 

  • Ireland Z, Russell A, Wallimann T, Walker D, Snow R (2009) Developmental changes in the expression of creatine synthesizing enzymes and creatine transporter in a precocial rodent, the spiny mouse. BMC Developmental Biology 9(1):39–50

    Article  PubMed  PubMed Central  Google Scholar 

  • Ireland Z, Castillo-Melendez M, Dickinson H, Snow R, Walker D (2011) A maternal diet supplemented with creatine from mid-pregnancy protects the newborn spiny mouse brain from birth hypoxia. Neuroscience 194:372–379

    CAS  Article  PubMed  Google Scholar 

  • King BF, Hastings RA (1977) The comparative fine structure of the interhemal membrane of chorioallantoic placentas from six genera of myomorph rodents. Am J Anat 149:165–179

    CAS  Article  PubMed  Google Scholar 

  • Li H, Thali RF, Smolak C, Gong F, Alzamora R, Wallimann T, Scholz R, Pastor-Soler NRM, Neumann D, Hallows KR (2010) Regulation of the creatine transporter by AMP-activated protein kinase in kidney epithelial cells. Am J Physiol-Renal Physiol 299:F167–F177

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Mellanby E (1913) The metabolism of lactating women. Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character, 88–109

  • Mihic S, Macdonald JR, McKenzie S, Tarnopolsky MA (2000) Acute creatine loading increases fat-free mass, but does not affect blood pressure, plasma creatinine, or CK activity in men and women. Med Sci Sports Exerc 32:291–296

    CAS  Article  PubMed  Google Scholar 

  • Morganti AA, Zervoudakis I, Letcher R, Romney B, von Oeyon P, Papera S, Sealey JE, Laragh JH (1980) Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy. Am J Med 68:97–104

    Article  PubMed  Google Scholar 

  • O’Connell B, Moritz K, Walker D, Dickinson H (2013) Sexually dimorphic placental development throughout gestation in the spiny mouse (Acomys cahirinus). Placenta 34:119–126

    Article  PubMed  Google Scholar 

  • Ouzounian JG, Elkayam U (2012) Physiologic changes during normal pregnancy and delivery. Cardiol Clin 30:317–329

    Article  PubMed  Google Scholar 

  • Perrin DH (2003) Creatine supplementation increases total body water without altering fluid distribution. J Athl Train 38:44–50

    PubMed  PubMed Central  Google Scholar 

  • Pritchard N, Kalra P (1998) Renal dysfunction accompanying oral creatine supplements. Lancet 352:233–234

    Article  Google Scholar 

  • Quinn TA, Ratnayake U, Dickinson H, Nguyen T-H, McIntosh M, Castillo-Melendez M, Conley AJ, Walker DW (2013) Ontogeny of the adrenal gland in the spiny mouse, with particular reference to production of the steroids cortisol and dehydroepiandrosterone. Endocrinology 154:1190–1201

    CAS  Article  PubMed  Google Scholar 

  • Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661

    CAS  Article  PubMed  Google Scholar 

  • Saunders NR, Dziegielewska KM, Møllgård K, Habgood MD, Wakefield MJ, Lindsay H, Stratzielle N, Ghersi-Egea J-F, Liddelow SA (2015) Influx mechanisms in the embryonic and adult rat choroid plexus: a transcriptome study. Front Neurosci 9

  • Snow RJ, Murphy RM (2001) Creatine and the creatine transporter: a review. Mol Cell Biochem 224:169–181

    CAS  Article  PubMed  Google Scholar 

  • Speer O, Neukomm LJ, Murphy RM, Zanolla E, Schlattner U, Henry H, Snow RJ, Wallimann T (2004) Creatine transporters: a reappraisal. Mol Cell Biochem 256:407–424

    Article  PubMed  Google Scholar 

  • Thornburg KL, Jacobson S-L, Giraud GD, Morton MJ (2000) Hemodynamic changes in pregnancy. Semin Perinatol 24:11–14

    CAS  Article  PubMed  Google Scholar 

  • Wallimann T, Tokarska-Schlattner M, Schlattner U (2011) The creatine kinase system and pleiotropic effects of creatine. Amino Acids, pp 1–26

  • Watt K, Garnham AP, Snow RJ (2004) Skeletal muscle total creatine content and creatine transporter gene expression in vegetarians prior to and following creatine supplementation. Int J Sport Nutr Exerc Metab 14:517

    CAS  PubMed  Google Scholar 

  • Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107–1213

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Funding from the National Health and Medical Research Council of Australia (APP1047504) to HD, DWW and RJS, the Cerebral Palsy Alliance to HD and DWW, and the Victorian Government’s Operational Infrastructure Support Program supported this work. HD is an NHMRC Career Development Fellow. SJE and DAL were supported by APA Scholarships during the completion of this study. DWW is supported by Cerebral Palsy Alliance and MMK was supported by a National Heart Foundation of Australia Fellowship at the time of this study.

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Affiliations

  1. The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright St, Clayton, Melbourne, 3168, Australia

    Stacey J. Ellery, Domenic A. LaRosa, David W. Walker & Hayley Dickinson

  2. Department of Obstetrics and Gynecology, Monash University, Monash Medical Centre, Clayton, Melbourne, Australia

    Stacey J. Ellery, Domenic A. LaRosa, David W. Walker & Hayley Dickinson

  3. Department of Physiology, Monash University, Clayton Campus, Melbourne, Australia

    Michelle M. Kett

  4. Centre for Physical Activity and Nutrition, Deakin University, Burwood Campus, Melbourne, Australia

    Paul A. Della Gatta & Rod J. Snow

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  1. Stacey J. Ellery
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  2. Domenic A. LaRosa
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  3. Michelle M. Kett
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  4. Paul A. Della Gatta
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  5. Rod J. Snow
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  6. David W. Walker
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  7. Hayley Dickinson
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Correspondence to Stacey J. Ellery.

Ethics declarations

All spiny mouse experiments were approved in advance by Monash University Animal Ethics Committee (MMCA2010/26) and conducted in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. All listed authors have read the final version of this manuscript and provide consent for publication.

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The authors declare that they have no conflict of interest.

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Handling Editor: T. Wallimann and R. Harris.

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Ellery, S.J., LaRosa, D.A., Kett, M.M. et al. Dietary creatine supplementation during pregnancy: a study on the effects of creatine supplementation on creatine homeostasis and renal excretory function in spiny mice. Amino Acids 48, 1819–1830 (2016). https://doi.org/10.1007/s00726-015-2150-7

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  • DOI: https://doi.org/10.1007/s00726-015-2150-7

Keywords

  • Nutrition
  • Cellular energy
  • Metabolism
  • Birth asphyxia
  • Fetal hypoxia