Article

Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation

Division of Medical Genetics, Department of Child Health, University of Missouri Health Care, Columbia, MO 65212, USA.
Molecular Genetics and Metabolism (Impact Factor: 2.83). 01/2012; 105(4):607-14. DOI: 10.1016/j.ymgme.2012.01.016
Source: PubMed

ABSTRACT Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most common mitochondrial disorders. Although the pathogenesis of stroke-like episodes remains unclear, it has been suggested that mitochondrial proliferation may result in endothelial dysfunction and decreased nitric oxide (NO) availability leading to cerebral ischemic events. This study aimed to assess NO production in subjects with MELAS syndrome and the effect of the NO precursors arginine and citrulline. Using stable isotope infusion techniques, we assessed arginine, citrulline, and NO metabolism in control subjects and subjects with MELAS syndrome before and after arginine or citrulline supplementation. The results showed that subjects with MELAS had lower NO synthesis rate associated with reduced citrulline flux, de novo arginine synthesis rate, and plasma arginine and citrulline concentrations, and higher plasma asymmetric dimethylarginine (ADMA) concentration and arginine clearance. We conclude that the observed impaired NO production is due to multiple factors including elevated ADMA, higher arginine clearance, and, most importantly, decreased de novo arginine synthesis secondary to decreased citrulline availability. Arginine and, to a greater extent, citrulline supplementation increased the de novo arginine synthesis rate, the plasma concentrations and flux of arginine and citrulline, and NO production. De novo arginine synthesis increased markedly with citrulline supplementation, explaining the superior efficacy of citrulline in increasing NO production. The improvement in NO production with arginine or citrulline supplementation supports their use in MELAS and suggests that citrulline may have a better therapeutic effect than arginine. These findings can have a broader relevance for other disorders marked by perturbations in NO metabolism.

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Available from: Ayman W El-Hattab, Jan 30, 2014
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    • "Nitric oxide (NO) is a biologic messenger produced by mammalian cells serving various regulatory functions including blood flow, platelet adhesion, immunity, and neurotransmission. There is growing evidence that NO deficiency occurs in at least some MD and can play a major role in the pathogenesis of stroke-like episodes, myopathy, diabetes mellitus, and lactic acidosis [3] [5] [6] [7] [8] [9] [10]. As such, NO measurements in patients with mitochondrial disease could be an important tool for understanding the pathogenesis and stages of the disease, assisting in the diagnosis, and "
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    ABSTRACT: Nitric oxide (NO) deficiency may occur in mitochondrial disorders (MD) and can contribute to the pathogenesis of the disease. It is difficult and invasive to measure systemic nitric oxide. NO is formed in the lungs and can be detected in expired air. Currently, hand-held fractional exhaled nitric oxide (FeNO) measurement devices are available enabling a fast in-office analysis of this non-invasive test. It was postulated that FeNO levels might be reduced in MD. Sixteen subjects with definite MD by modified Walker criteria (4 to 30 years of age) and sixteen healthy control subjects of similar age, race and body mass index (BMI) underwent measurement of FeNO in accordance with the American Thoracic Society guidelines. Sixteen patient-control pairs were recruited. The median FeNO level was 6.5 ppm (IQR: 4-9.5) and 10.5 ppm (IQR: 8-20.5) in the MD and control groups, respectively. In 13 pairs (81%), the FeNO levels were lower in the MD cases than in the matched controls (p=0.021). Eleven (69%) cases had very low FeNO levels (≤7ppm) compared to only 1 control (p=0.001). All cases with enzymatic deficiencies in complex I had FeNO ≤7ppm. Single-breath exhaled nitric oxide recordings were decreased in patients with MD. This pilot study suggests that hand-held FeNO measurements could be an attractive non-invasive indicator of MD. In addition, measurement of FeNO could be used as a parameter to monitor therapeutic response in this population.
    The Open Respiratory Medicine Journal 11/2013; 7(6):67-70. DOI:10.2174/1874306401307010067
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    • "In addition, there may be shunting of NO into reactive nitrogen species formation (Naini et al., 2005; Sproule and Kaufmann, 2008; Vattemi et al., 2011). Finally, there may be decreased availability of the NO precursors arginine and citrulline (Naini et al., 2005; Koga et al., 2006; El-Hattab et al., 2012a). "
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    ABSTRACT: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder in which nitric oxide (NO) deficiency may play a role in the pathogenesis of several complications including stroke-like episodes and lactic acidosis. Supplementing the NO precursors arginine and citrulline restores NO production in MELAS syndrome. In this study we evaluated the effect of arginine or citrulline on lactic acidemia in adults with MELAS syndrome. Plasma lactate decreased significantly after citrulline supplementation, whereas the effect of arginine supplementation did not reach statistical significance. These results support the potential therapeutic utility of arginine and citrulline in MELAS syndrome and suggest that citrulline supplementation may be more efficacious. However, therapeutic efficacy of these compounds should be further evaluated in clinical trials.
    Mitochondrion 11/2013; 13(6):898. DOI:10.1016/j.mito.2013.07.004 · 3.52 Impact Factor
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    • "). Finally, there may be decreased availability of the NO precursors arginine and citrulline (Naini et al., 2005; Koga et al., 2006; El-Hattab et al., 2012a). "
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    ABSTRACT: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder in which nitric oxide (NO) deficiency may play a role in the pathogenesis of several complications including stroke-like episodes and lactic acidosis. Supplementing the NO precursors arginine and citrulline restores NO production in MELAS syndrome. In this study we evaluated the effect of arginine or citrulline on lactic acidemia in adults with MELAS syndrome. Plasma lactate decreased significantly after citrulline supplementation, whereas the effect of arginine supplementation did not reach statistical significance. These results support the potential therapeutic utility of arginine and citrulline in MELAS syndrome and suggest that citrulline supplementation may be more efficacious. However, therapeutic efficacy of these compounds should be further evaluated in clinical trials.
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