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Voluntary Exercise Prevents Oxidative Stress in the Brain of Phenylketonuria Mice

  • Research Report
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JIMD Reports, Volume 27

Part of the book series: JIMD Reports ((JIMD,volume 27))

Abstract

Background: High phenylalanine levels in phenylketonuria (PKU) have been associated with brain oxidative stress and amino acid imbalance. Exercise has been shown to improve brain function in hyperphenylalaninemia and neurodegenerative diseases. This study aimed to verify the effects of exercise on coordination and balance, plasma and brain amino acid levels, and brain oxidative stress markers in PKU mice.

Methods: Twenty wild-type (WT) and 20 PAHenu2 (PKU) C57BL/6 mice were placed in cages with (exercise, Exe) or without (sedentary, Sed) running wheels during 53 days. At day 43, a balance beam test was performed. Plasma and brain were collected for analyses of amino acid levels and the oxidative stress parameters superoxide dismutase (SOD) activity, sulfhydryl and reduced glutathione (GSH) contents, total radical-trapping antioxidant potential (TRAP), and total antioxidant reactivity (TAR).

Results: SedPKU showed poor coordination (p < 0.001) and balance (p < 0.001), higher plasma and brain phenylalanine (p < 0.001), and increased brain oxidative stress (p < 0.05) in comparison to SedWT. ExePKU animals ran less than ExeWT (p = 0.018). Although no improvement was seen in motor coordination and balance, exercise in PKU restored SOD, sulfhydryl content, and TRAP levels to controls. TAR levels were increased in ExePKU in comparison to SedPKU (p = 0.012). Exercise decreased plasma and brain glucogenic amino acids in ExePKU, but did not change plasma and brain phenylalanine in both WT and PKU.

Conclusions: Exercise prevents oxidative stress in the brain of PKU mice without modifying phenylalanine levels. Hence, exercise positively affects the brain, demonstrating its value as an intervention to improve brain quality in PKU.

Competing interests: None declared

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Abbreviations

BCAA:

Branched-chain amino acid

Exe:

Exercise

GSH:

Reduced glutathione

PAH:

Phenylalanine hydroxylase

Phe:

Phenylalanine

PKU:

Phenylketonuria

Sed:

Sedentary

SOD:

Superoxide dismutase

TAR:

Total antioxidant reactivity

TRAP:

Total radical-trapping antioxidant potential

WT:

Wild type

References

  • Aksenov MY, Markesbery WR (2001) Changes in thiol content and expression of glutathione redox system genes in the hippocampus and cerebellum in Alzheimer’s disease. Neurosci Lett 302:141–145

    Article  CAS  PubMed  Google Scholar 

  • Ang ET, Tai YK, Lo SQ, Seet R, Soong TW (2010) Neurodegenerative diseases: exercising toward neurogenesis and neuroregeneration. Front Aging Neurosci 2:25

    PubMed  PubMed Central  Google Scholar 

  • Browne RW, Armstrong D (1998) Reduced glutathione and glutathione disulfide. Methods Mol Biol 108:347–352

    CAS  PubMed  Google Scholar 

  • Carter RJ, Lione LA, Humby T et al (1999) Characterization of progressive motor deficits in mice transgenic for the human Huntington’s disease mutation. J Neurosci 19:3248–3257

    CAS  PubMed  Google Scholar 

  • Chang YK, Liu S, Yu HH, Lee YH (2012) Effect of acute exercise on executive function in children with attention deficit hyperactivity disorder. Arch Clin Neuropsychol 27:225–237

    Article  PubMed  Google Scholar 

  • Clark PJ, Brzezinska WJ, Thomas MW, Ryzhenko NA, Toshkov SA, Rhodes JS (2008) Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6J mice. Neuroscience 155:1048–1058

    Article  CAS  PubMed  Google Scholar 

  • de Groot MJ, Hoeksma M, Blau N, Reijngoud DJ, van Spronsen FJ (2010) Pathogenesis of cognitive dysfunction in phenylketonuria: review of hypotheses. Mol Genet Metab 99(Suppl 1):S86–S89

    Article  PubMed  Google Scholar 

  • Durrant JR, Seals DR, Connell ML et al (2009) Voluntary wheel running restores endothelial function in conduit arteries of old mice: direct evidence for reduced oxidative stress, increased superoxide dismutase activity and down-regulation of NADPH oxidase. J Physiol 587:3271–3285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elokda AS, Nielsen DH (2007) Effects of exercise training on the glutathione antioxidant system. Eur J Cardiovasc Prev Rehabil 14:630–637

    Article  PubMed  Google Scholar 

  • Ercal N, Aykin-Burns N, Gurer-Orhan H, McDonald JD (2002) Oxidative stress in a phenylketonuria animal model. Free Radic Biol Med 32:906–911

    Article  CAS  PubMed  Google Scholar 

  • Evelson P, Travacio M, Repetto M, Escobar J, Llesuy S, Lissi EA (2001) Evaluation of total reactive antioxidant potential (TRAP) of tissue homogenates and their cytosols. Arch Biochem Biophys 388:261–266

    Article  CAS  PubMed  Google Scholar 

  • Fernandes CG, Leipnitz G, Seminotti B et al (2010) Experimental evidence that phenylalanine provokes oxidative stress in hippocampus and cerebral cortex of developing rats. Cell Mol Neurobiol 30:317–326

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez MJ, Gutierrez AP, Gassio R, Fuste ME, Vilaseca MA, Campistol J (2011) Neurological complications and behavioral problems in patients with phenylketonuria in a follow-up unit. Mol Genet Metab 104(Suppl):S73–S79

    Article  CAS  PubMed  Google Scholar 

  • Graham TE, MacLean DA (1998) Ammonia and amino acid metabolism in skeletal muscle: human, rodent and canine models. Med Sci Sports Exerc 30:34–46

    Article  CAS  PubMed  Google Scholar 

  • Hagen MEK, Pederzolli CD, Sgaravatti AM et al (2002) Experimental hyperphenylalaninemia provokes oxidative stress in rat brain. Biochim Biophys Acta 1586:344–352

    Article  Google Scholar 

  • Jahja R, Huijbregts SC, de Sonneville LM, van der Meere JJ, van Spronsen FJ (2014) Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria. J Pediatr 164:895.e2–899.e2

    Article  Google Scholar 

  • Kim DI, Kim KS (2013) Walnut extract exhibits anti-fatigue action via improvement of exercise tolerance in mice. Lab Anim Res 29:190–195

    Article  PubMed  PubMed Central  Google Scholar 

  • Kirk-Sanchez NJ, McGough EL (2014) Physical exercise and cognitive performance in the elderly: current perspectives. Clin Interv Aging 9:51–62

    PubMed  PubMed Central  Google Scholar 

  • Lin TW, Kuo YM (2013) Exercise benefits brain function: the monoamine connection. Brain Sci 3:39–53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Marklund SL (1985) Pyrogallol autoxidation. In: Greenwald RA (ed) Handbook of methods for oxygen radical research. CRC, Boca Raton, pp 243–247

    Google Scholar 

  • Martynyuk AE, van Spronsen FJ, Van der Zee EA (2010) Animal models of brain dysfunction in phenylketonuria. Mol Genet Metab 99(Suppl 1):S100–S105

    Article  CAS  PubMed  Google Scholar 

  • Mazzola PN, Terra M, Rosa AP et al (2011) Regular exercise prevents oxidative stress in the brain of hyperphenylalaninemic rats. Metab Brain Dis 26:291–297

    Article  CAS  PubMed  Google Scholar 

  • Meneguello MO, Mendonca JR, Lancha AH Jr, Costa Rosa LF (2003) Effect of arginine, ornithine and citrulline supplementation upon performance and metabolism of trained rats. Cell Biochem Funct 21:85–91

    Article  CAS  PubMed  Google Scholar 

  • Moraes TB, Zanin F, da Rosa A et al (2010) Lipoic acid prevents oxidative stress in vitro and in vivo by an acute hyperphenylalaninemia chemically-induced in rat brain. J Neurol Sci 292:89–95

    Article  CAS  PubMed  Google Scholar 

  • Moraes TB, Dalazen GR, Jacques CE, de Freitas RS, Rosa AP, Dutra-Filho CS (2014) Glutathione metabolism enzymes in brain and liver of hyperphenylalaninemic rats and the effect of lipoic acid treatment. Metab Brain Dis 29:609–615

    CAS  PubMed  Google Scholar 

  • Mulder CK, Papantoniou C, Gerkema MP, Van Der Zee EA (2014) Neither the SCN nor the adrenals are required for circadian time-place learning in mice. Chronobiol Int 31:1075–1092

    Article  PubMed  PubMed Central  Google Scholar 

  • Ney DM, Hull AK, van Calcar SC, Liu X, Etzel MR (2008) Dietary glycomacropeptide supports growth and reduces the concentrations of phenylalanine in plasma and brain in a murine model of phenylketonuria. J Nutr 138:316–322

    CAS  PubMed  Google Scholar 

  • Petzinger GM, Fisher BE, McEwen S, Beeler JA, Walsh JP, Jakowec MW (2013) Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson’s disease. Lancet Neurol 12:716–726

    Article  PubMed  PubMed Central  Google Scholar 

  • Piscopo P, Crestini A, Adduci A et al (2011) Altered oxidative stress profile in the cortex of mice fed an enriched branched-chain amino acids diet: possible link with amyotrophic lateral sclerosis? J Neurosci Res 89:1276–1283

    Article  CAS  PubMed  Google Scholar 

  • Qin M, Smith CB (2007) Regionally selective decreases in cerebral glucose metabolism in a mouse model of phenylketonuria. J Inherit Metab Dis 30:318–325

    Article  CAS  PubMed  Google Scholar 

  • Radak Z, Kumagai S, Taylor AW, Naito H, Goto S (2007) Effects of exercise on brain function: role of free radicals. Appl Physiol Nutr Metab 32:942–946

    Article  CAS  PubMed  Google Scholar 

  • Radak Z, Hart N, Sarga L et al (2010) Exercise plays a preventive role against Alzheimer’s disease. J Alzheimers Dis 20:777–783

    PubMed  Google Scholar 

  • Ribas GS, Sitta A, Wajner M, Vargas CR (2011) Oxidative stress in phenylketonuria: what is the evidence? Cell Mol Neurobiol 31:653–662

    Article  CAS  PubMed  Google Scholar 

  • Sanayama Y, Nagasaka H, Takayanagi M et al (2011) Experimental evidence that phenylalanine is strongly associated to oxidative stress in adolescents and adults with phenylketonuria. Mol Genet Metab 103:220–225

    Article  CAS  PubMed  Google Scholar 

  • Sawin EA, Murali SG, Ney DM (2014) Differential effects of low-phenylalanine protein sources on brain neurotransmitters and behavior in C57Bl/6-Pah(enu2) mice. Mol Genet Metab 111:452–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schulpis KH, Tsakiris S, Traeger-Synodinos J, Papassotiriou I (2005) Low total antioxidant status is implicated with high 8-hydroxy-2-deoxyguanosine serum concentrations in phenylketonuria. Clin Biochem 38:239–242

    Article  CAS  PubMed  Google Scholar 

  • Sierra C, Vilaseca MA, Moyano D et al (1998) Antioxidant status in hyperphenylalaninemia. Clin Chim Acta 276:1–9

    Article  CAS  PubMed  Google Scholar 

  • Sitta A, Barschak AG, Deon M et al (2009a) L-carnitine blood levels and oxidative stress in treated phenylketonuric patients. Cell Mol Neurobiol 29:211–218

    Article  CAS  PubMed  Google Scholar 

  • Sitta A, Manfredini V, Biasi L et al (2009b) Evidence that DNA damage is associated to phenylalanine blood levels in leukocytes from phenylketonuric patients. Mutat Res 679:13–16

    Article  CAS  PubMed  Google Scholar 

  • Soderling SH, Langeberg LK, Soderling JA et al (2003) Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice. Proc Natl Acad Sci U S A 100:1723–1728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solverson P, Murali SG, Brinkman AS et al (2012) Glycomacropeptide, a low-phenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic stress in the murine model of phenylketonuria. Am J Physiol Endocrinol Metab 302:E885–E895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Souza LC, Filho CB, Goes AT et al (2013) Neuroprotective effect of physical exercise in a mouse model of Alzheimer’s disease induced by beta-amyloid(1)(-)(4)(0) peptide. Neurotox Res 24:148–163

    Article  CAS  PubMed  Google Scholar 

  • Stroth S, Reinhardt RK, Thone J et al (2010) Impact of aerobic exercise training on cognitive functions and affect associated to the COMT polymorphism in young adults. Neurobiol Learn Mem 94:364–372

    Article  CAS  PubMed  Google Scholar 

  • Surtees R, Blau N (2000) The neurochemistry of phenylketonuria. Eur J Pediatr 159(Suppl 2):S109–S113

    Article  CAS  PubMed  Google Scholar 

  • Takeda K, Machida M, Kohara A, Omi N, Takemasa T (2011) Effects of citrulline supplementation on fatigue and exercise performance in mice. J Nutr Sci Vitaminol 57:246–250

    Article  CAS  PubMed  Google Scholar 

  • Tsou YH, Shih CT, Ching CH et al (2015) Treadmill exercise activates Nrf2 antioxidant system to protect the nigrostriatal dopaminergic neurons from MPP+ toxicity. Exp Neurol 263:50–62

    Article  CAS  PubMed  Google Scholar 

  • van Bakel MM, Printzen G, Wermuth B, Wiesmann UN (2000) Antioxidant and thyroid hormone status in selenium-deficient phenylketonuric and hyperphenylalaninemic patients. Am J Clin Nutr 72:976–981

    PubMed  Google Scholar 

  • van Spronsen FJ, Hoeksma M, Reijngoud DJ (2009) Brain dysfunction in phenylketonuria: is phenylalanine toxicity the only possible cause? J Inherit Metab Dis 32:46–51

    Article  PubMed  Google Scholar 

  • van Vliet D, Anjema K, Jahja R et al (2015) BH4 treatment in BH4-responsive PKU patients: preliminary data on blood prolactin concentrations suggest increased cerebral dopamine concentrations. Mol Genet Metab 114:29–33

    Article  PubMed  Google Scholar 

  • Vilaseca MA, Lambruschini N, Gomez-Lopez L et al (2010) Quality of dietary control in phenylketonuric patients and its relationship with general intelligence. Nutr Hosp 25:60–66

    CAS  PubMed  Google Scholar 

  • Weglage J, Fromm J, van Teeffelen-Heithoff A et al (2013) Neurocognitive functioning in adults with phenylketonuria: results of a long term study. Mol Genet Metab 110(Suppl):S44–S48

    Article  CAS  PubMed  Google Scholar 

  • Wipfli B, Landers D, Nagoshi C, Ringenbach S (2011) An examination of serotonin and psychological variables in the relationship between exercise and mental health. Scand J Med Sci Sports 21:474–481

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research project has been made possible thanks to a fellowship from PKU Academy under the auspices of EXCEMED, Excellence in Medical Education, the Abel Tasman Talent Program from the University Medical Center Groningen and the University of Groningen. We thank Pim de Blaauw for the amino acid analyses and Wanda Douwenga and Jan Keijser for their technical support.

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Authors and Affiliations

  1. Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES) – University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands

    Priscila Nicolao Mazzola, Vibeke Bruinenberg & Eddy A. van der Zee

  2. Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Priscila Nicolao Mazzola, Karen Anjema, Danique van Vliet & Francjan J. van Spronsen

  3. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

    Priscila Nicolao Mazzola & Carlos Severo Dutra-Filho

Authors
  1. Priscila Nicolao Mazzola
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  2. Vibeke Bruinenberg
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  3. Karen Anjema
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  4. Danique van Vliet
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  5. Carlos Severo Dutra-Filho
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  6. Francjan J. van Spronsen
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  7. Eddy A. van der Zee
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Corresponding author

Correspondence to Priscila Nicolao Mazzola .

Editor information

Editors and Affiliations

  1. Tulane University Medical School, New Orleans, Louisiana, USA

    Eva Morava

  2. Division of Metabolism and Children’s Re, University Children's Hospital Zurich, Zurich, Switzerland

    Matthias Baumgartner

  3. Division of Child and Adolescent Neurolo, Mayo Clinic, Rochester, Minnesota, USA

    Marc Patterson

  4. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, United Kingdom

    Shamima Rahman

  5. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Baden-Württemberg, Germany

    Verena Peters

Additional information

Communicated by: Nenad Blau, PhD

Concise 1: Sentence Take-Home Message

Voluntary training improved brain oxidative stress and reduced brain and plasma glucogenic amino acids in phenylketonuria mice without changing phenylalanine levels.

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Conflict of Interest

Priscila Nicolao Mazzola, Vibeke Bruinenberg, Karen Anjema, Danique van Vliet, Carlos Severo Dutra-Filho, Francjan J. van Spronsen, and Eddy A. van der Zee declare that they have no conflict of interest.

Animal Rights

All institutional and national guidelines for the care and use of laboratory animals were followed.

Details of the Contribution of Individual Authors

Priscila Nicolao Mazzola, Vibeke Bruinenberg, Karen Anjema, and Danique van Vliet collected the data. Priscila Nicolao Mazzola performed the statistical analyses and drafted the manuscript. All authors participated in the study design, contributed to the interpretation of the results, and revised the manuscript.

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Mazzola, P.N. et al. (2015). Voluntary Exercise Prevents Oxidative Stress in the Brain of Phenylketonuria Mice. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 27. JIMD Reports, vol 27. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_498

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  • DOI: https://doi.org/10.1007/8904_2015_498

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  • Print ISBN: 978-3-662-50408-6

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