title: Oxidative stress and pathology in muscular dystrophies: focus on protein thiol oxidation and dysferlinopathies.
abstract: 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.
authors: School of Anatomy, Physiology and Human Biology, University of Western Australia, Perth, Western Australia, Australia.
authors: Jessica R
authors: JR
authors: Terrill
authors: Hannah G
authors: HG
authors: Radley-Crabb
authors: Tomohito
authors: T
authors: Iwasaki
authors: Frances A
authors: FA
authors: Lemckert
authors: Peter G
authors: PG
authors: Arthur
authors: Miranda D
authors: MD
authors: Grounds
mesh_terms: D000818:Animals; D000073939:Dysferlin; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D009136:Muscular Dystrophies / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000378:metabolism
chemical_list: C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds
keywords: Duchenne muscular dystrophy; Dysferlinopathies; N-acetylcysteine; antioxidants; dystropathology; muscle necrosis; oxidative stress; protein thiol oxidation; reactive oxygen species; skeletal muscle