The effects of reactive oxygen species (ROS) on the regulation of akt signalling: implications for the maintenance of muscle mass

Pearl Tan

Research output: ThesisDoctoral Thesis

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Abstract

[Truncated abstract] Ageing results in the loss of skeletal muscle mass, strength and function, a condition known as sarcopenia. With an increasingly elderly population, sarcopenia is emerging as a major health concern, with loss of independence for individuals and high health costs for the community. Thus there is a compelling need to understand the molecular mechanisms underlying sarcopenia and to develop effective therapeutic interventions. One of the many factors proposed to contribute to sarcopenia is elevated oxidative stress. Oxidative stress, caused by excess reactive oxygen species (ROS), has been proposed as a key intermediary in depressing protein synthesis and thus contributing to the loss of muscle mass. One possibility is that oxidative stress can blunt signalling pathways that promote protein synthesis, such as the key IGF-1 signalling pathway. A mechanism by which ROS can affect signalling pathways involves the reversible thiol oxidation of signalling proteins sensitive to ROS. The first part of this thesis investigated the effects of ROS on the IGF-1 signalling pathway. Using a C2C12 myotube culture model, levels of ROS were modulated with antioxidant and oxidant treatments. The phosphorylation level of Akt(Ser473), a downstream target of IGF-1 signalling, was examined as a readout for the effects of ROS. Increased ROS did not blunt the ability of IGF-1 to stimulate Akt(Ser473) phosphorylation. However, basal level of Akt(Ser473) phosphorylation was affected by ROS. Unexpectedly, both increased and decreased ROS stimulated Akt(Ser473) phosphorylation. To explain the apparent paradox, I analysed the oxidation states of Akt and PTEN (a phosphatase upstream of Akt). These proteins were chosen on the basis of previous studies suggesting that Akt and PTEN can be reversibly oxidised by ROS.
Original languageEnglish
QualificationDoctor of Philosophy
Publication statusUnpublished - 2013

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