Hafner et al. 2016.pdf (1.13 MB)
Improved muscle function in Duchenne muscular dystrophy through L-arginine and metformin: an investigator-initiated, open-label, single-center, proof-of-concept-study
journal contribution
posted on 2023-05-18, 16:26 authored by Hafner, P, Bonati, U, Erne, B, Schmid, M, Rubino, D, Pohlman, U, Peters, T, Rutz, E, Frank, S, Neuhaus, C, Deuster, S, Gloor, M, Bieri, O, Fishcmann, A, Sinnerich, M, Nuri GuvenNuri Guven, Fischer, DAltered 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.
History
Publication title
PLoS OneVolume
11Article number
e0147634Number
e0147634Pagination
1-19ISSN
1932-6203Department/School
School of Pharmacy and PharmacologyPublisher
Public Library of SciencePlace of publication
United StatesRights statement
Copyright: © 2016 Hafner et al. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/Repository Status
- Open