title: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT02516085.
authors.affiliation: Division of Neuropaediatrics, University of Basel Children's Hospital, Basel, Switzerland.|Department of Neurology, University of Basel Hospital, Basel, Switzerland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hafner
authors.affiliation: Division of Neuropaediatrics, University of Basel Children's Hospital, Basel, Switzerland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bonati
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Erne
authors.affiliation: Division of Neuropaediatrics, University of Basel Children's Hospital, Basel, Switzerland.
authors.forename: Maurice
authors.initials: M
authors.lastname: Schmid
authors.affiliation: Division of Neuropaediatrics, University of Basel Children's Hospital, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rubino
authors.affiliation: Division of Neuropaediatrics, University of Basel Children's Hospital, Basel, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Pohlman
authors.affiliation: Interdisciplinary Center of Nutritional and Metabolic Diseases, St. Claraspital, Basel, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Peters
authors.affiliation: Paediatric Orthopaedic Department, University of Basel Children's Hospital, Basel, Switzerland.
authors.forename: Erich
authors.initials: E
authors.lastname: Rutz
authors.affiliation: Division of Neuropathology, Institute of Pathology, University of Basel Hospital, Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Frank
authors.affiliation: Therapy Department, University of Basel Children's Hospital, Basel, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Neuhaus
authors.affiliation: Hospital Pharmacy, University of Basel Hospital, Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Deuster
authors.affiliation: Department of Radiology, Division of Radiological Physics, University of Basel Hospital, Basel, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Gloor
authors.affiliation: Department of Radiology, Division of Radiological Physics, University of Basel Hospital, Basel, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bieri
authors.affiliation: Division of Neuroradiology, University of Basel Hospital, Basel, Switzerland.
authors.forename: Arne
authors.initials: A
authors.lastname: Fischmann
authors.affiliation: Department of Neurology, University of Basel Hospital, Basel, Switzerland.|Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Sinnreich
authors.affiliation: Pharmacy, School of Medicine, University of Tasmania, Hobart, TAS, Australia.
authors.forename: Nuri
authors.initials: N
authors.lastname: Gueven
authors.affiliation: Division of Neuropaediatrics, University of Basel Children's Hospital, Basel, Switzerland.|Department of Neurology, University of Basel Hospital, Basel, Switzerland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Fischer
mesh_terms: D001120:Arginine / Q000008:administration & dosage / Q000627:therapeutic use*; D001706:Biopsy; D002648:Child; D004359:Drug Therapy, Combination; D006801:Humans; D008279:Magnetic Resonance Imaging; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy*; D052248:Nitric Oxide Synthase Type I / Q000187:drug effects; D010865:Pilot Projects
chemical_list: D008687:Metformin; D001120:Arginine; D052248:Nitric Oxide Synthase Type I