Journal
BRAIN
Volume 135, Issue -, Pages 1115-1127Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/aws036
Keywords
antioxidant response; myopathies; oxidative stress; neuromuscular disorders
Categories
Funding
- National Institutes of Health [1K08AR054835, R01NS54731, AG-020591]
- Child Neurology Foundation
- National Science Foundation (NSF) [0725976]
- Endostem
- ANR (Agence Nationale pour la Recherche, MyCa)
- INSERM (Institut National de la Sante et la Recherche Medicale)
- AP-HP (Assistance Publique-Hopitaux de Paris, Contrat d'Interface)
- Direct For Biological Sciences [0725976] Funding Source: National Science Foundation
- Division Of Integrative Organismal Systems [0725976] Funding Source: National Science Foundation
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The skeletal muscle ryanodine receptor is an essential component of the excitation-contraction coupling apparatus. Mutations in RYR1 are associated with several congenital myopathies (termed RYR1-related myopathies) that are the most common non-dystrophic muscle diseases of childhood. Currently, no treatments exist for these disorders. Although the primary pathogenic abnormality involves defective excitation-contraction coupling, other abnormalities likely play a role in disease pathogenesis. In an effort to discover novel pathogenic mechanisms, we analysed two complementary models of RYR1-related myopathies, the relatively relaxed zebrafish and cultured myotubes from patients with RYR1-related myopathies. Expression array analysis in the zebrafish disclosed significant abnormalities in pathways associated with cellular stress. Subsequent studies focused on oxidative stress in relatively relaxed zebrafish and RYR1-related myopathy myotubes and demonstrated increased oxidant activity, the presence of oxidative stress markers, excessive production of oxidants by mitochondria and diminished survival under oxidant conditions. Exposure to the antioxidant N-acetylcysteine reduced oxidative stress and improved survival in the RYR1-related myopathies human myotubes ex vivo and led to significant restoration of aspects of muscle function in the relatively relaxed zebrafish, thereby confirming its efficacy in vivo. We conclude that oxidative stress is an important pathophysiological mechanism in RYR1-related myopathies and that N-acetylcysteine is a successful treatment modality ex vivo and in a vertebrate disease model. We propose that N-acetylcysteine represents the first potential therapeutic strategy for these debilitating muscle diseases.
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