Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy

Dowling, J.J., Arbogast, S., Hur, J., Nelson, D.D., McEvoy, A., Waugh, T., Marty, I., Lunardi, J., Brooks, S.V., Kuwada, J.Y., and Ferreiro, A.
Brain : a journal of neurology   135(4): 1115-1127 (Journal)
Registered Authors
Dowling, Jim, Kuwada, John
antioxidant response, myopathies, oxidative stress, neuromuscular disorders
MeSH Terms
  • Acetophenones/pharmacology
  • Acetylcysteine/therapeutic use*
  • Animals
  • Animals, Genetically Modified
  • Antioxidants/therapeutic use*
  • Behavior, Animal
  • Disease Models, Animal
  • Enzyme Inhibitors/pharmacology
  • Humans
  • Indomethacin/pharmacology
  • Larva
  • Microarray Analysis
  • Microscopy, Electron, Transmission
  • Mitochondria/ultrastructure
  • Muscle Contraction/genetics
  • Muscle Fibers, Skeletal/drug effects
  • Muscle Fibers, Skeletal/metabolism
  • Muscle Fibers, Skeletal/pathology
  • Muscle Fibers, Skeletal/ultrastructure
  • Muscle Proteins/genetics
  • Muscle Proteins/metabolism
  • Muscular Diseases/drug therapy*
  • Muscular Diseases/genetics
  • Muscular Diseases/metabolism*
  • Muscular Diseases/pathology
  • Mutation/genetics
  • Oxidative Stress/drug effects*
  • Oxidative Stress/genetics
  • Ryanodine Receptor Calcium Release Channel/genetics
  • Ryanodine Receptor Calcium Release Channel/metabolism*
  • Zebrafish
22418739 Full text @ Brain

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.

Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes