Improved Muscle Function in Duchenne Muscular Dystrophy through L-Arginine and Metformin: An Investigator-Initiated, Open-Label, Single-Center, Proof-Of-Concept-Study

Abstract

Altered neuronal nitric oxide synthase function in Duchenne muscular dystrophy leads to impaired mitochondrial function which is thought to be one cause of muscle damage in this disease. The study tested if increased intramuscular nitric oxide concentration can improve mitochondrial energy metabolism in Duchenne muscular dystrophy using a novel therapeutic approach through the combination of L-arginine with metformin. Five ambulatory, genetically confirmed Duchenne muscular dystrophy patients aged between 7–10 years were treated with L-arginine (3 x 2.5 g/d) and metformin (2 x 250 mg/d) for 16 weeks. Treatment effects were assessed using mitochondrial protein expression analysis in muscular biopsies, indirect calorimetry, Dual-Energy X-Ray Absorptiometry, quantitative thigh muscle MRI, and clinical scores of muscle performance. There were no serious side effects and no patient dropped out. Muscle biopsy results showed pre-treatment a significantly reduced mitochondrial protein expression and increased oxidative stress in Duchenne muscular dystrophy patients compared to controls. Post-treatment a significant elevation of proteins of the mitochondrial electron transport chain was observed as well as a reduction in oxidative stress. Treatment also decreased resting energy expenditure rates and energy substrate use shifted from carbohydrates to fatty acids. These changes were associated with improved clinical scores. In conclusion pharmacological stimulation of the nitric oxide pathway leads to improved mitochondria function and clinically a slowing of disease progression in Duchenne muscular dystrophy. This study shall lead to further development of this novel therapeutic approach into a real alternative for Duchenne muscular dystrophy patients.Trial RegistrationClinicalTrials.gov NCT02516085

Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration

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Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

“…When combined with deflazacort, L-Arginine prevented exercise-induced damage and induced a persistent functional improvement in distance run in mdx mice. Recently, a small cohort of DMD boys aged 7–10 treated with L-Arginine and metformin for 16 weeks showed significantly increased mitochondrial protein expression and reduced in oxidative stress 172 . Other supplements investigated to improve muscle strength by providing metabolic support include creatine and glutamine, which have been shown to increase grip strength 173 and decrease protein degradation 174 , respectively, in DMD boys.…”

Impaired Bioenergetics in Clinical Medicine: A Target to Tackle

“…Oral L-arginine, another precursor of creatine, positively affected energy metabolism in MELAS syndrome, an inherited disorder of mitochondrial energy metabolism (Rodan et al 2015), while its effectiveness to improve brain bioenergetics in patients with X-linked creatine transporter defect was absent (Fons et al 2008) or minimal (Chilosi et al 2012). Improved muscle bioenergetics and mitochondrial function have been reported recently in children suffering from Duchenne muscular dystrophy treated with L-arginine and metformin for 16 weeks (Hafner et al 2016). …”