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Amino Acids

, Volume 47, Issue 9, pp 1853–1863 | Cite as

The l-arginine/NO pathway and homoarginine are altered in Duchenne muscular dystrophy and improved by glucocorticoids

  • Irina Hörster
  • Katharina Weigt-Usinger
  • Christina Carmann
  • Kristine Chobanyan-Jürgens
  • Cornelia Köhler
  • Ulrike Schara
  • Arslan Arinc Kayacelebi
  • Bibiana Beckmann
  • Dimitrios Tsikas
  • Thomas Lücke
Original Article
Part of the following topical collections:
  1. Homoarginine, Arginine and Relatives

Abstract

The l-arginine/nitric oxide (L-Arg/NO) pathway regulates endothelial function and may play an important role in the pathogenesis of Duchenne muscular dystrophy (DMD). Yet, this pathway is poorly investigated in children suffering from DMD. Endothelial dysfunction can affect the perfusion of contracting muscles, thus leading to ischemia and hypoxia. In the present study, we tested the hypothesis that reduced NO production due to elevated synthesis of N G,N G-dimethyl-l-arginine (asymmetric dimethylarginine, ADMA), an endogenous inhibitor of NO synthesis, is a possible pathophysiological mechanism for progressive intramuscular muscle ischemia and disturbed endothelial function in children with DMD. Given the possible antagonistic action of homoarginine (hArg) on ADMA, we also analyzed this amino acid. We investigated 55 male patients with DMD and 54 healthy male controls (HC; aged 11.9 ± 4.8 vs. 11.1 ± 4.9 years, mean ± SD). Urinary creatinine and metabolites of the L-Arg/NO pathway were measured in plasma and urine by GC–MS or GC–MS/MS. Urine levels of ADMA and its major urinary metabolite dimethylamine (DMA), nitrite and nitrate (P < 0.001 for all) and hArg (P = 0.002) were significantly higher in DMD patients compared to HC, while the urinary DMA/ADMA molar ratio was lower (P = 0.002). In plasma, nitrate (P < 0.001), hArg (P = 0.002) and the hArg/ADMA ratio (P < 0.001) were lower in DMD than in HC. In plasma, ADMA (631 ± 119 vs. 595 ± 129 nM, P = 0.149), arginine and nitrite did not differ between DMD and HC. In DMD, positive correlations between ADMA, DMA or nitrate excretion and the stage of disease (according to Vignos and Thompson) were found. In DMD patients on steroid medication, lower concentrations of ADMA in plasma, and of DMA, ADMA, nitrate and hArg in urine were observed compared to non-treated patients. The L-Arg/NO pathway is impaired in DMD patients, with the disease progression being clinically negatively correlated with the extent of impairment. One of the underlying mechanisms in DMD may involve insufficient antagonism of ADMA by hArg. Steroids, but not creatine supplementation, seems to improve the L-Arg/NO pathway in DMD.

Keywords

ADMA Children Duchenne muscular dystrophy Homoarginine Nitric oxide Steroids 

Abbreviations

ACE

Angiotensin-converting enzyme

ADMA

Asymmetric dimethylarginine (N G,N G-dimethyl-l-arginine)

AGAT

Arginineglycine amidinotransferase

DDAH

Dimethylarginine dimethylaminohydrolase

DMA

Dimethylamine

DMD

Duchenne muscular dystrophy

EDRF

Endothelium-derived relaxing factor

GAMT

Guanidinoacetate N-methyltransferase

GC–MS

Gas chromatography–mass spectrometry

GC–MS/MS

Gas chromatography–tandem mass spectrometry

hArg

Homoarginine

NO

Nitric oxide

NOS

Nitric oxide synthase

SDMA

Symmetric dimethylarginine (N G,N -dimethyl-l-arginine)

sVCAM-1

Soluble vascular cell adhesion molecule-1

Notes

Acknowledgments

The authors thank A. Mitschke and M. T. Suchy for excellent laboratory assistance and F. M. Gutzki for performing GC–MS and GC–MS/MS analyses. We are also grateful for the support in recruiting DMD patients from the Department of Neuropediatrics in the University Hospital Essen.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

The Ethics Committees of the Faculty of Medicine at Ruhr-University Bochum and of the Hannover Medical School approved the study. Written consent was given by each participant and his parents or only by the participant if he was 18 years or older.

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Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Irina Hörster
    • 1
  • Katharina Weigt-Usinger
    • 1
  • Christina Carmann
    • 1
  • Kristine Chobanyan-Jürgens
    • 2
  • Cornelia Köhler
    • 1
  • Ulrike Schara
    • 3
  • Arslan Arinc Kayacelebi
    • 2
  • Bibiana Beckmann
    • 2
  • Dimitrios Tsikas
    • 2
  • Thomas Lücke
    • 1
  1. 1.Department of Neuropediatrics, University Children’s HospitalRuhr-University BochumBochumGermany
  2. 2.Centre of Pharmacology and ToxicologyHannover Medical SchoolHannoverGermany
  3. 3.Department of NeuropediatricsUniversity Hospital EssenEssenGermany

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