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

James J. Dowling, Sandrine Arbogast, Junguk Hur, Darcee D. Nelson, Anna McEvoy, Trent Waugh, Isabelle Marty, Joel Lunardi, Susan V. Brooks, John Y. Kuwada, Ana Ferreiro

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1115-1127
Number of pages13
JournalBrain
Volume135
Issue number4
DOIs
StatePublished - Apr 2012

Fingerprint

Muscular Diseases
Oxidative Stress
Antioxidants
Zebrafish
Skeletal Muscle Fibers
Acetylcysteine
Oxidants
Excitation Contraction Coupling
Muscles
Therapeutics
Myotonia Congenita
Ryanodine Receptor Calcium Release Channel
Survival
Vertebrates
Mitochondria
Skeletal Muscle
Mutation

Keywords

  • antioxidant response
  • myopathies
  • neuromuscular disorders
  • oxidative stress

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Dowling, J. J., Arbogast, S., Hur, J., Nelson, D. D., McEvoy, A., Waugh, T., ... Ferreiro, A. (2012). Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy. Brain, 135(4), 1115-1127. https://doi.org/10.1093/brain/aws036

Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy. / Dowling, James J.; Arbogast, Sandrine; Hur, Junguk; Nelson, Darcee D.; McEvoy, Anna; Waugh, Trent; Marty, Isabelle; Lunardi, Joel; Brooks, Susan V.; Kuwada, John Y.; Ferreiro, Ana.

In: Brain, Vol. 135, No. 4, 04.2012, p. 1115-1127.

Research output: Contribution to journalArticle

Dowling, JJ, Arbogast, S, Hur, J, Nelson, DD, McEvoy, A, Waugh, T, Marty, I, Lunardi, J, Brooks, SV, Kuwada, JY & Ferreiro, A 2012, 'Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy', Brain, vol. 135, no. 4, pp. 1115-1127. https://doi.org/10.1093/brain/aws036
Dowling JJ, Arbogast S, Hur J, Nelson DD, McEvoy A, Waugh T et al. Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy. Brain. 2012 Apr;135(4):1115-1127. https://doi.org/10.1093/brain/aws036
Dowling, James J. ; Arbogast, Sandrine ; Hur, Junguk ; Nelson, Darcee D. ; McEvoy, Anna ; Waugh, Trent ; Marty, Isabelle ; Lunardi, Joel ; Brooks, Susan V. ; Kuwada, John Y. ; Ferreiro, Ana. / Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy. In: Brain. 2012 ; Vol. 135, No. 4. pp. 1115-1127.
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