Effects of single and combined metformin and l-citrulline supplementation on l-arginine-related pathways in Becker muscular dystrophy patients: possible biochemical and clinical implications

Hanff, Erik; Hafner, Patricia; Bollenbach, Alexander; Bonati, Ulrike; Kayaçelebi, Arslan Arinç; Fischer, Dirk; Tsikas, Dimitrios

doi:10.1007/s00726-018-2614-7

Cited by 22 publications

(46 citation statements)

References 73 publications

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“…Interestingly, a recent study also showed that the levels of L-arginine and its precursor L-citrulline were significantly lower in mdx muscles with respect to wild type ones [64]. A recent study showed that L-homoarginine (one of the direct products of L-Arg metabolism in human) serum levels were significantly lower in Becker muscular dystrophy patients [61]. This evidence, if confirmed in DMD patients, might give more support to the requirement of L-arginine and L-citrulline supplementation through diet.…”

Section: L-arginine and L-citrullinementioning

confidence: 99%

“…Utrophin has a similar function in the maintenance of the dystrophin-glycoprotein complex (DGC) integrity and myofibre structure. A widespread strategy to improve utrophin expression was to enhance the activity of the muscular isoform of nitric oxide synthase (NOS-μ) and NO synthesis by means of NO-donors administration, like L-arginine (or its precursor, L-citrulline [60,61]). NO is also critical to support mitochondrial function and biogenesis [62,63].…”

Section: L-arginine and L-citrullinementioning

confidence: 99%

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Safety issues and harmful pharmacological interactions of nutritional supplements in Duchenne muscular dystrophy: considerations for Standard of Care and emerging virus outbreaks

Boccanegra

Verhaart

Cappellari

et al. 2020

Pharmacological Research

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At the moment, little treatment options are available for Duchenne muscular dystrophy (DMD). The absence of the dystrophin protein leads to a complex cascade of pathogenic events in myofibres, including chronic inflammation and oxidative stress as well as altered metabolism. The attention towards dietary supplements in DMD is rapidly increasing, with the aim to counteract pathology-related alteration in nutrient intake, the consequences of catabolic distress or to enhance the immunological response of patients as nowadays for the COVID-19 pandemic emergency. By definition, supplements do not exert therapeutic actions, although a great confusion may arise in daily life by the improper distinction between supplements and therapeutic compounds. For most supplements, little research has been done and little evidence is available concerning their effects in DMD as well as their preventing actions against infections. Often these are not prescribed by clinicians and patients/caregivers do not discuss the use with their clinical team. Then, little is known about the real extent of supplement use in DMD patients. It is mistakenly assumed that, since compounds are of natural origin, if a supplement is not effective, it will also do no harm. However, supplements can have serious side effects and also have harmful interactions, in terms of reducing efficacy or leading to toxicity, with other therapies. It is therefore pivotal to shed light on this unclear scenario for the sake of patients. This review discusses the supplements mostly used by DMD patients, focusing on their potential toxicity, due to a variety of mechanisms including pharmacodynamic or pharmacokinetic interactions and contaminations, as well as on reports of adverse events. This overview underlines the need for caution in uncontrolled use of dietary supplements in fragile populations such as DMD patients. A culture of appropriate use has to be implemented between clinicians and patients' groups.

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Section: L-arginine and L-citrullinementioning

confidence: 99%

Section: L-arginine and L-citrullinementioning

confidence: 99%

Safety issues and harmful pharmacological interactions of nutritional supplements in Duchenne muscular dystrophy: considerations for Standard of Care and emerging virus outbreaks

Boccanegra

Verhaart

Cappellari

et al. 2020

Pharmacological Research

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“…In patients with Becker muscular dystrophy (BMD) the measured baseline creatinine-corrected urinary excretion rates were 48.8 (group I) and 53.0 (group II) µmol/mmol for DMA and 5.75 (group I) and 8.05 (group II) µmol/mmol for ADMA, and the corresponding DMA/ADMA molar ratios were 8.49 and 6.58 ( Table 1 ) [ 37 ]. Treatment of the BMD patients with metformin, L-citrulline and their combination did not result in appreciable changes in the urinary excretion rates of DMA and ADMA or their ratio [ 37 ].…”

Section: Urinary Dma and Adma In Children Adolescents And Adults mentioning

confidence: 99%

“…At physiological urinary concentrations, DMA (IC 50 , 590 µM), TMA (IC 50 , 53 µM) and creatinine (IC 50 , 6.8 mM) were found to inhibit the in vitro transport of metformin [ 60 ], suggesting a potential role of DMA in the renal reabsorption of organic cations. Yet, pharmacological metformin (3 × 500 mg/d) did not change the DMA excretion in patients with Becker muscular dystrophy (BMD), suggesting no mutual interaction of metformin and DMA on the renal OCT2 activity [ 37 ]. Pharmacological acetazolamide (5 mg/kg), which is a strong inhibitor of the activity of carbonic anhydrase (IC 50 , 12 nM for carbonic anhydrase II), seems to also not affect the excretion of DMA in the proximal tubule ( Figure 3 ).…”

Section: Statins Metformin L-arginine Catecholamines and The Prmentioning

confidence: 99%

Urinary Dimethylamine (DMA) and Its Precursor Asymmetric Dimethylarginine (ADMA) in Clinical Medicine, in the Context of Nitric Oxide (NO) and Beyond

Tsikas

2020

JCM

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Asymmetric protein-arginine dimethylation is a major post-translational modification (PTM) catalyzed by protein-arginine methyltransferase (PRMT). Regular proteolysis releases asymmetric dimethylarginine (ADMA). Of the daily produced ADMA, about 10% are excreted unchanged in the urine. The remaining 90% are hydrolyzed by dimethylarginine dimethylaminohydrolase (DDAH) to L-citrulline and dimethylamine (DMA), which is readily excreted in the urine. The PRMT/DDAH pathway is almost the exclusive origin of urinary ADMA and the major source of urinary DMA. Dietary fish and seafood represent additional abundant sources of urinary DMA. The present article provides an overview of urinary ADMA and DMA reported thus far in epidemiological, clinical and pharmacological studies, in connection with the L-arginine/nitric oxide (NO) pathway and beyond, in neonates, children and adolescents, young and elderly subjects, males and females. Discussed diseases mainly include those relating to the renal and cardiovascular systems such as peripheral arterial occlusive disease, coronary artery disease, chronic kidney disease, rheumatoid arthritis, Becker muscular disease, Duchenne muscular disease (DMD), attention deficit hyperactivity disorder (ADHD), and type I diabetes. Under standardized conditions involving the abstinence of DMA-rich fresh and canned fish and seafood, urinary DMA and ADMA are useful as measures of whole-body asymmetric arginine-dimethylation in health and disease. The creatinine-corrected excretion rates of DMA range from 10 to 80 µmol/mmol in adults and up to 400 µmol/mmol in children and adolescents. The creatinine-corrected excretion rates of ADMA are on average 10 times lower. In general, diseases are associated with higher urinary DMA and ADMA excretion rates, and pharmacological treatment, such as with steroids and creatine (in DMD), decreases their excretion rates, which may be accompanied by a decreased urinary excretion of nitrate, the major metabolite of NO. In healthy subjects and in rheumatoid arthritis patients, the urinary excretion rate of DMA correlates positively with the excretion rate of dihydroxyphenylglycol (DHPG), the major urinary catecholamines metabolite, suggesting a potential interplay in the PRMT/DDAH/NO pathway.

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“…[35][36][37][38][39][40] Alternatively, administration of L-citrulline, a dietary amino acid which is converted to L-arginine and has higher bioavailability than L-arginine alone, 41 improves clinical scores in patients with Becker muscular dystrophy. 42 Based on this evidence it is surprising that the effects of increasing NO production on GI function in vivo have not been examined. As compounds increasing NOS1 activity could improve GI function in muscular dystrophy and enhance quality of life for patients, we used video imaging and spatiotemporal (ST) mapping to interrogate GI dysfunction in mdx mice and determine the therapeutic potential of dietary L-arginine or L-citrulline supplementation.…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal Mapping Reveals Regional Gastrointestinal Dysfunction in mdx Dystrophic Mice Ameliorated by Oral L-arginine Supplementation

Swiderski

Bindon

Trieu

et al. 2020

J Neurogastroenterol Motil

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Background/Aims Patients with Duchenne muscular dystrophy exhibit significant, ongoing impairments in gastrointestinal (GI) function likely resulting from dysregulated nitric oxide production. Compounds increasing neuronal nitric oxide synthase expression and/or activity could improve GI dysfunction and enhance quality of life for dystrophic patients. We used video imaging and spatiotemporal mapping to identify GI dysfunction in mdx dystrophic mice and determine whether dietary intervention to enhance nitric oxide could alleviate aberrant colonic activity in muscular dystrophy. Methods Four-week-old male C57BL/10 and mdx mice received a specialized diet either with no supplementation (control) or supplemented (1 g/kg/day) with L-alanine, L-arginine, or L-citrulline for 8 weeks. At the conclusion of treatment, mice were sacrificed by cervical dislocation and colon motility examined by spatiotemporal (ST) mapping ex vivo. Results ST mapping identified increased contraction number in the mid and distal colon of mdx mice on control and L-alanine supplemented diets relative to C57BL/10 mice (P < 0.05). Administration of either L-arginine or L-citrulline attenuated contraction number in distal colons of mdx mice relative to C57BL/10 mice. Conclusions GI dysfunction in Duchenne muscular dystrophy has been sadly neglected as an issue affecting quality of life. ST mapping identified regional GI dysfunction in the mdx dystrophic mouse. Dietary interventions to increase nitric oxide signaling in the GI tract reduced the number of colonic contractions and alleviated colonic constriction at rest. These findings in mdx mice reveal that L-arginine can improve colonic motility and has potential therapeutic relevance for alleviating GI discomfort, improving clinical care, and enhancing quality of life in Duchenne muscular dystrophy.

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Effects of single and combined metformin and l-citrulline supplementation on l-arginine-related pathways in Becker muscular dystrophy patients: possible biochemical and clinical implications

Cited by 22 publications

References 73 publications

Safety issues and harmful pharmacological interactions of nutritional supplements in Duchenne muscular dystrophy: considerations for Standard of Care and emerging virus outbreaks

Safety issues and harmful pharmacological interactions of nutritional supplements in Duchenne muscular dystrophy: considerations for Standard of Care and emerging virus outbreaks

Urinary Dimethylamine (DMA) and Its Precursor Asymmetric Dimethylarginine (ADMA) in Clinical Medicine, in the Context of Nitric Oxide (NO) and Beyond

Spatiotemporal Mapping Reveals Regional Gastrointestinal Dysfunction in mdx Dystrophic Mice Ameliorated by Oral L-arginine Supplementation

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