Neuropediatrics 2015; 46 - PS02-34
DOI: 10.1055/s-0035-1550745

Improved Muscle Function in Duchenne Muscular Dystrophy using a Combination of L-Arginine and Metformin

U. Bonati 1, P. Hafner 1, B. Erne 2, E. Thomas 3, E. Rutz 4, S. Frank 5, C. Hilker 6, S. Deuster 6, M. Gloor 7, O. Bieri 7, M. Sinnreich 8, A. Fischmann 7, D. Fischer 1
  • 1Abt. für Neuro- und Entwicklungspädiatrie, Universitäts Kinderspiatl beider Basel, Basel, Switzerland
  • 2Department of Biomedicine, University of Basel, Basel, Switzerland
  • 3Department of Pediatric Anesthesia, Universitäts Kinderspiatl beider Basel, Basel, Switzerland
  • 4Department of Pediatric Orthopaedic, Universitäts Kinderspiatl beider Basel, Basel, Switzerland
  • 5Department of Neuropathology, University Hospital Basel, Basel, Switzerland
  • 6University Hospital Basel, Hospital Pharmacy, Basel, Switzerland
  • 7Department of Radiology, University of Basel Hospital, Basel, Switzerland
  • 8Department of Neurology, University Hospital Basel, Basel, Switzerland

Objective: Duchenne muscular dystrophy (DMD) is the most common and one of the most severe muscular dystrophies presenting with rapidly progressing muscle wasting and premature death. Reduced neuronal nitric oxide synthase (nNOS) activity is thought to be important for the pathophysiology of DMD. In this prospective, open-label, single center proof-of-concept pilot study, we aimed to increase the intramuscular NO concentration to improve the mitochondrial energy metabolism using a novel approach with a combination of l-arginine and metformin.

Methods: A total of five ambulatory, genetically confirmed DMD patients between the ages of 7to 10 years were treated with l-arginine (3 × 2.5 g/d) and metformin (2 × 250 mg/d) for 16 weeks. Treatment effects were assessed using protein expression analysis in muscular biopsies, indirect calorimetry, dual-energy X-ray absorptiometry, quantitative thigh muscle MRI, and clinical scores of muscle performance.

Results: There were no serious side effects and no patient dropped out. Before treatment, we found a significant reduced mitochondrial protein expression and increased oxidative stress in DMD muscle biopsies compared with controls. Treatment of DMD patients resulted in significant elevations of cGMP and mitochondrial proteins of complex III and V. There was also a consistent response in all muscle biopsy samples with increase of nitrotyrosin, complex II and IV, and reduced oxidative stress. Resting energy expenditure rates decreased and the energy substrate use shifted from carbohydrate to fatty acid use. These changes were associated with improved clinical scores (motor function and timed walking distances) in four of five patients. These improvements exceed the ones reported for the standard symptomatic steroid treatment of care.

Conclusion: Pharmacological stimulation of the NO pathway seems a promising strategy to ameliorate molecular deficits, improve muscle performance, and to slow disease progression in DMD.

Keywords: Duchenne muscular dystrophy, biomarker, NO pathway, mitochondria function.