The role of oxidative stress and protein thiol oxidation in the skeletal muscle pathology of mice with muscular dystrophies

    Research output: ThesisDoctoral Thesis

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    Abstract

    [Truncated abstract] The muscular dystrophies comprise more than 30 different clinical disorders that are characterised 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 can cause cellular damage by directly and irreversibly damaging macromolecules such as proteins, membrane lipids and DNA. Whilst it is well established that irreversible oxidative damage of protein and lipids is implicated in Duchenne Muscular Dystrophy (DMD), there is very little research into oxidative damage for the dysferlinopathies. Also lacking in the literature, is the role of another major consequence of oxidative stress ‐ oxidation of cysteine residues of key proteins called protein thiol oxidation, which can affect many aspects of molecular function, in either DMD or the dysferlinopathies. This thesis developed methods to evaluate the role of elevated oxidative stress in DMD and dysferlinopathies, and presents novel data for the involvement of protein thiol oxidation. Using the mdx mouse model for DMD and the A/J dysferlin deficient (A/Jdysf‐/‐) mouse model for dysferlinopathies, it was established that, while there is a degree of irreversible protein damage in both models, the most dramatic consequence of oxidative stress in the skeletal muscle tissue is excessive protein thiol oxidation, located within the myofibres, suggesting an important role in the pathology of both disorders. It was thus hypothesised that prevention of protein thiol oxidation via treatment with cysteine precursors will lead to an improvement in pathology in the mdx mouse model for DMD.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2013

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