Effect of Combination l-Citrulline and Metformin Treatment on Motor Function in Patients With Duchenne Muscular Dystrophy

Abstract

Key PointsQuestionDoes treatment with l-citrulline and metformin combination therapy reduce motor function decline in ambulant patients with Duchenne muscular dystrophy?FindingsIn this randomized clinical trial of 47 ambulant male children aged 6.5 to 10 years with Duchenne muscular dystrophy, treatment with a combination of l-citrulline and metformin therapies provided a clinically relevant but not statistically significant reduction in motor function decline, as assessed by the transfer and standing posture dimension of the Motor Function Measure scale. No indications of harm were found in the intention-to-treat population.MeaningTreatment with a combination of l-citrulline and metformin therapies may slow muscle function decline in a specific subgroup of patients with Duchenne muscular dystrophy, but additional clinical trials with greater statistical power are warranted.

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

“…It will therefore be very important in the near future to determine whether treatment with metformin can improve dystrophic cardiomyopathy in the advanced stage of the pathology. To conclude, our data support the concept that metformin alone or in combination with other drugs might be a potential therapeutic strategy to ameliorate the dystrophinopathies (Casteels et al, 2010 ; Ljubicic and Jasmin, 2015 ; Hafner et al, 2016 , 2019 ; Mantuano et al, 2018 ; Vitiello et al, 2019 ).…”

“…We here tested metformin, an antidiabetic drug with pleiotropic properties that are related to its mitochondrial effects (for review see Foretz et al, 2014 ; Vial et al, 2019 ). Long-term treatment with metformin has already demonstrated some beneficial effects on motor function in stable DMD patients with encouraging evidence regarding muscle degeneration and histopathology (Hafner et al, 2016 , 2019 ). The exact mechanisms of action of metformin have yet to be elucidated; however, at high doses, metformin inhibits the oxidation of NADH at the complex I level.…”

“…Therefore, targeting mitochondrial function and/or metabolism in DMD has become a therapeutic issue over the last decade. Among the therapeutic candidates, the antidiabetic drug metformin has recently been evaluated in DMD both in preclinical studies and in clinical trials (Ljubicic and Jasmin, 2015 ; Hafner et al, 2016 , 2019 ; Mantuano et al, 2018 ; Vitiello et al, 2019 ). This N,N-dimethylbiguanide interferes with the activity of mitochondrial complex I and activates AMP-activated protein kinase (AMPK), a critical hub for metabolic-mediated signaling pathways (for a review, see Foretz et al, 2014 ).…”

“…This N,N-dimethylbiguanide interferes with the activity of mitochondrial complex I and activates AMP-activated protein kinase (AMPK), a critical hub for metabolic-mediated signaling pathways (for a review, see Foretz et al, 2014 ). Although the variability of the severity profile and the different stages of the pathology will require larger-scale clinical trials, treatment with metformin in combination with nitric oxide precursors has shown encouraging positive effects, particularly on motor function (Hafner et al, 2019 ). In mdx mice, long-term treatment with metformin alone also improves diaphragm function and limits muscle damage and the development of fibrosis due to exercise (Mantuano et al, 2018 ).…”

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents

“…In vitro, metformin protected the myotubes from cardiotoxin induced degeneration [ 118 , 119 ]. A Phase I clinical trial (NCT02516085) completed in 2012 in Switzerland showed slowing of the disease process in DMD patients but no change in motor function [ 120 , 121 ]. Adiponectin is decreased in mdx mice and DMD patients [ 122 , 123 ] and is widely recognized as an insulin sensitizer.…”