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Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy
- Source :
- Brain-A Journal of Neurology, Brain-A Journal of Neurology, 2012, 135 (Pt 4), pp.1115-27. ⟨10.1093/brain/aws036⟩, Brain-A Journal of Neurology, Oxford University Press (OUP), 2012, 135 (Pt 4), pp.1115-27. ⟨10.1093/brain/aws036⟩
- Publication Year :
- 2012
-
Abstract
- International audience; 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.
- Subjects :
- MESH: Muscle Contraction
Indomethacin
Muscle Fibers, Skeletal
Muscle Proteins
Mitochondrion
neuromuscular disorders
medicine.disease_cause
Antioxidants
MESH: Ryanodine Receptor Calcium Release Channel
Animals, Genetically Modified
0302 clinical medicine
MESH: Behavior, Animal
MESH: Animals
Enzyme Inhibitors
Zebrafish
0303 health sciences
MESH: Indomethacin
MESH: Muscle Fibers, Skeletal
MESH: Oxidative Stress
biology
Behavior, Animal
Myogenesis
3. Good health
Cell biology
Mitochondria
MESH: Enzyme Inhibitors
Larva
myopathies
MESH: Microscopy, Electron, Transmission
medicine.symptom
Muscle Contraction
medicine.medical_specialty
MESH: Mutation
antioxidant response
MESH: Mitochondria
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
MESH: Animals, Genetically Modified
03 medical and health sciences
MESH: Muscle Proteins
MESH: Acetylcysteine
Microscopy, Electron, Transmission
Muscular Diseases
In vivo
Internal medicine
medicine
Animals
Humans
Myopathy
MESH: Zebrafish
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
030304 developmental biology
RYR1
MESH: Humans
MESH: Antioxidants
MESH: Muscular Diseases
Acetophenones
Ryanodine Receptor Calcium Release Channel
Original Articles
biology.organism_classification
Microarray Analysis
Acetylcysteine
MESH: Microarray Analysis
Disease Models, Animal
Oxidative Stress
Endocrinology
MESH: Acetophenones
Mutation
Neurology (clinical)
MESH: Disease Models, Animal
MESH: Larva
030217 neurology & neurosurgery
Ex vivo
Oxidative stress
Subjects
Details
- ISSN :
- 14602156 and 00068950
- Volume :
- 135
- Issue :
- Pt 4
- Database :
- OpenAIRE
- Journal :
- Brain : a journal of neurology
- Accession number :
- edsair.doi.dedup.....a637d29fa4e973d79e44657df83a0d5a