Disruption of redox relays in the age-related failure of muscle responses to contractile activity

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We propose to study the role that a process called a 'redox relay' plays in the response of skeletal muscles to exercise and how this changes with age. Exercise is important in helping to maintain the health of our skeletal muscles and it is well known that skeletal muscle responds to exercise and to other environmental changes in a positive way to make the muscles stronger and work more efficiently. Muscle does this by increasing or decreasing the content of different proteins that are produced after exercise. Unfortunately as we age, these adaptations following exercise become less efficient, increasingly leading to a failure to maintain muscle mass and function.As muscle exercises it generates some very reactive molecules, called reactive oxygen species, and it is known that these species can act as signals to initiate some of the positive adaptations that exercise induces in muscle. Unfortunately the precise way in which these reactive species undertake this is unknown, as is how these actions change as we age. One of these reactive species is hydrogen peroxide which is present in muscles at very low amounts and is the most important of these signalling molecules. Our research team has a great deal of experience of studying hydrogen peroxide and other similar species in muscle and we have previously shown in general terms how important these species are to maintaining muscle integrity following exercise and we also demonstrated that this process appears to become disrupted as we age. Recent studies have shown that a small number of proteins present in our muscles can react with hydrogen peroxide and can transmit an oxidising signal from hydrogen peroxide to other key proteins with which hydrogen peroxide cannot react directly. The process that these intermediary proteins undertake is called a "redox relay" and the proposed project will examine the way that these "redox relay" proteins can transfer the oxidising signal from hydrogen peroxide. It will identify which proteins are able to do this, which other proteins they then react with to transfer the signal and which then go on to stimulate positive adaptations in the muscle. Finally we will determine how this process is modified by ageing. The initial part of the project will involve detailed molecular studies that require us to modify proteins in muscles in order to understand their actions and this will be undertaken in mice. Once we have identified the pathways involved we will then examine key aspects of these that can be measured in muscle biopsy samples that we will obtain from healthy young and older human subjects undertaking exercise. On completion of the project we should understand how these signals are transmitted in muscle following exercise to stimulate positive adaptations in the muscle and how they are changed by ageing and their relevance to the poor responses elderly subjects have to exercise. This information will facilitate the design of logical and targeted interventions to correct the ageing changes with potential benefits of maintaining muscle strength in the elderly.