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

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.

Asymmetric dimethylarginine is not a marker of arterial damage in children with glomerular kidney diseases

“…We found significantly lower ADMA levels in patients treated with GC, though this relation was not dose-dependent and was not confirmed in multivariate model. Similar results were found in children with Duchenne muscular dystrophy [32]. On the contrary, Japanese authors showed [33].…”

Skeletal muscle quantitative nuclear magnetic resonance imaging and spectroscopy as an outcome measure for clinical trials (part II)

“…При изучении мышц ног гипертензив-ных животных было показано, что ASL позволяет ко-личественно точно определить изменение вазодилатации [157]. Изменение перфузии является патологической особенностью при ПМД Дюшенна [158], в частности связанной с нарушением образования оксида азота [159,160], также отчасти из-за фиброзных изменений [91]. Возможность неинвазивно измерять в клинических исследованиях перфузию скелетных мышц у пациентов с ПМД Дюшенна представляет интерес в случаях необ-ходимости оценки эффективности сосудорасширяю-щих и антисклеротических препаратов [94,161,162].…”

Therapies that are available and under development for Duchenne muscular dystrophy: What about lung function?

“…Furthermore, recent research has identified a potential role of L‐Arg/NO in the pathogenesis of this disorder, since its impaired function results in endothelial dysfunction, affects negatively the perfusion of contracting muscles and leads to ischemia and hypoxia. Indeed, supplementation with steroids seems to restore this pathway and increase nitric oxide production and vasodilatory activity . Steroids mainly used in these preclinical studies were prednisone or prednisolone (the active form of prednisone after hepatic metabolism).…”

“…Indeed, supplementation with steroids seems to restore this pathway and increase nitric oxide production and vasodilatory activity. 41 Steroids mainly used in these preclinical studies were prednisone or prednisolone (the active form of prednisone after hepatic metabolism).…”