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

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

Author information

1
Division of Neuropaediatrics, University of Basel Children's Hospital, Basel, Switzerland.
2
Department of Neurology, University of Basel Hospital, Basel, Switzerland.
3
Department of Biomedicine, University of Basel, Basel, Switzerland.
4
Interdisciplinary Center of Nutritional and Metabolic Diseases, St. Claraspital, Basel, Basel, Switzerland.
5
Paediatric Orthopaedic Department, University of Basel Children's Hospital, Basel, Switzerland.
6
Division of Neuropathology, Institute of Pathology, University of Basel Hospital, Basel, Switzerland.
7
Therapy Department, University of Basel Children's Hospital, Basel, Switzerland.
8
Hospital Pharmacy, University of Basel Hospital, Basel, Switzerland.
9
Department of Radiology, Division of Radiological Physics, University of Basel Hospital, Basel, Switzerland.
10
Division of Neuroradiology, University of Basel Hospital, Basel, Switzerland.
11
Pharmacy, School of Medicine, University of Tasmania, Hobart, TAS, Australia.

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.

PMID:
26799743
PMCID:
PMC4723144
DOI:
10.1371/journal.pone.0147634
[Indexed for MEDLINE]
Free PMC Article

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