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

PLoS One. 2016 Jan 22;11(1):e0147634. doi: 10.1371/journal.pone.0147634. eCollection 2016.

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 registration: ClinicalTrials.gov NCT02516085.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arginine / administration & dosage
  • Arginine / therapeutic use*
  • Biopsy
  • Child
  • Drug Therapy, Combination
  • Humans
  • Magnetic Resonance Imaging
  • Metformin / administration & dosage
  • Metformin / therapeutic use*
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Muscular Dystrophy, Duchenne / drug therapy*
  • Nitric Oxide Synthase Type I / drug effects
  • Pilot Projects

Substances

  • Metformin
  • Arginine
  • Nitric Oxide Synthase Type I

Associated data

  • ClinicalTrials.gov/NCT02516085

Grant support

PH and UB were supported by grants of the University of Basel (https://medizin.unibas.ch/lehre/nachwuchsfoerderung.html) DF was supported by the Lorenzo-Piaggio Foundation, Switzerland; the Thomi-Hopf-Stiftung, Switzerland (www.thomi-hopf-stiftung.ch); the Neuromuscular Research Association Basel, Switzerland (http://www.nerab.org/); the University of Basel Children’s Hospital, and the Department of Neurology, University Hospital Basel. The Department of Diagnostic and Interventional Radiology (AF) is supported by a grant from Bracco Suisse SA (http://imaging.bracco.com/ch-en/bracco-suisse-sa). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.