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The Mode of Action of Metformin and L-Citrullin on Muscle Metabolism in Duchenne Muscular Dystrophy. A Biomarker Study.

Research Project
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01.01.2014
 - 31.08.2014

Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder leading to relentless muscle wasting and premature death in affected children. The only currently available symptomatic treatment for DMD consists of corticosteroids, resulting in modest beneficial effects but relevant side effects. In DMD dystrophin expression is lost disrupting the normal cytoskeletal structure. To date a lot is known about the structural consequences auf DMD, e.g. destabilization of the dystrophin associated glycoprotein complex resulting in muscles fibres that are more sensitive to mechanical damage and thus degenerate. Still very little is known about the metabolic consequences of dystrophin loss which is associated with a severe reduction of neuronal nitric oxide (NO) synthase (nNOS). NO stimulates the up-regulation of nuclear genes involved in mitochondrial biogenesis and ATP generation. In a small pilot trial with 5 DMD patients we tested if NO precursors as the amino acids L-arginine and the biguanide antidiabetic drug metformin (indirect nNOS activator) can improve muscle function and influence metabolism in DMD. We observed an improved lipid metabolism, improved functional abilities and prolonged walking distances in the 2 min walking distance. Quantitative muscle magnet resonance imaging (MRI) indicated a slowing in muscle degeneration in these patients. Our results thus indicate that there is a potential of treating the disturbed cell metabolism in DMD. To prove these results in a larger cohort, we will start soon an investigator driven double-blind placebo controlled randomized clinical trial (RCT) in DMD. 40 DMD patients will be randomised for a 26 week (1:1) trial. L-citrulline instead of L-arginine will be used, as it was demonstrated that in humans L-citrulline increases the L-arginine and NO concentrations more than L-arginine itself. As the mode of action of L-citrulline and metformin on cell metabolism in DMD is still poorly understood the proposed project forms a sub-project of this trial to examine markers of nitric oxide metabolism, mitochondrial function and energy production, carbohydrate and fatty utilization ratios, and oxidative stress markers in urine and blood samples to better define the pharmacological pathways of the drug combination, and to search for metabolic biomarkers in DMD. Quantitative muscle MRI will be used to observe how close changes in cell metabolism and muscle degeneration are linked. In case of positive results of the main trial a more effective and safer symptomatic treatment will be available in DMD and a better understanding of the cell metabolism in DMD might help to improve or even develop new drugs for DMD and related myopathies.

Members (5)

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Ulrike Bonati

Principal Investigator
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Dirk Fischer

Principal Investigator
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Arne Fischmann

Co-Investigator
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Oliver Bieri

Project Member
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Michael Sinnreich

Project Member