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Oxidative stress and pathology in muscular dystrophies: focus on protein thiol oxidation and dysferlinopathies
Author(s) -
Terrill Jessica R.,
RadleyCrabb Hannah G.,
Iwasaki Tomohito,
Lemckert Frances A.,
Arthur Peter G.,
Grounds Miranda D.
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12142
Subject(s) - oxidative stress , mdx mouse , duchenne muscular dystrophy , reactive oxygen species , muscular dystrophy , oxidative phosphorylation , dystrophin , context (archaeology) , lipofuscin , biochemistry , chemistry , biology , microbiology and biotechnology , medicine , paleontology
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 D uchenne muscular dystrophy, and we have recently identified increased protein thiol oxidation in dystrophic muscles of the mdx mouse model for D uchenne muscular dystrophy. This review evaluates the role of elevated oxidative stress in D uchenne 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.