Oxidative stress and pathology in muscular dystrophies: focus on protein thiol oxidation and dysferlinopathies

The muscular dystrophies comprise more than 30 clinical disorders that are characterized by progressive skeletal muscle wasting and degeneration. Although the genetic basis for many of these disorders has been identified, the exact mechanism for pathogenesis generally remains unknown. It is consider...

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Published in:The FEBS journal 2013-09, Vol.280 (17), p.4149-4164
Main Authors: Terrill, Jessica R., Radley‐Crabb, Hannah G., Iwasaki, Tomohito, Lemckert, Frances A., Arthur, Peter G., Grounds, Miranda D.
Format: Article
Language:English
Subjects:
Animals
antioxidants
Duchenne muscular dystrophy
Dysferlin
Dysferlinopathies
dystropathology
Humans
Membrane Proteins - physiology
Mice
Mice, Inbred mdx
Mice, Knockout
muscle necrosis
Muscular Dystrophies - metabolism
Muscular Dystrophies - pathology
Muscular dystrophy
N‐acetylcysteine
Oxidation-Reduction
Oxidative Stress
Pathology
protein thiol oxidation
Proteins
reactive oxygen species
Reactive Oxygen Species - metabolism
skeletal muscle
Sulfhydryl Compounds - chemistry
Sulfhydryl Compounds - metabolism
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Summary:The muscular dystrophies comprise more than 30 clinical disorders that are characterized by progressive skeletal muscle wasting and degeneration. Although the genetic basis for many of these disorders has been identified, the exact mechanism for pathogenesis generally remains unknown. It is considered that disturbed levels of reactive oxygen species (ROS) contribute to the pathology of many muscular dystrophies. Reactive oxygen species and oxidative stress may cause cellular damage by directly and irreversibly damaging macromolecules such as proteins, membrane lipids and DNA; another major cellular consequence of reactive oxygen species is the reversible modification of protein thiol side chains that may affect many aspects of molecular function. Irreversible oxidative damage of protein and lipids has been widely studied in Duchenne muscular dystrophy, and we have recently identified increased protein thiol oxidation in dystrophic muscles of the mdx mouse model for Duchenne muscular dystrophy. This review evaluates the role of elevated oxidative stress in Duchenne muscular dystrophy and other forms of muscular dystrophies, and presents new data that show significantly increased protein thiol oxidation and high levels of lipofuscin (a measure of cumulative oxidative damage) in dysferlin‐deficient muscles of A/J mice at various ages. The significance of this elevated oxidative stress and high levels of reversible thiol oxidation, but minimal myofibre necrosis, is discussed in the context of the disease mechanism for dysferlinopathies, and compared with the situation for dystrophin‐deficient mdx mice. Disturbed levels of reactive oxygen species are believed to contribute to the pathology of many muscular dystrophies. New data are presented that show significantly increased protein thiol oxidation and high levels of lipofuscin (a measure of cumulative oxidative damage) in dysferlin‐deficient muscles of A/J mice at various ages. The significance of this is critically compared with dystrophin‐deficient mdx mice.
ISSN:1742-464X
1742-4658
DOI:10.1111/febs.12142