Mitochondrial reactive oxygen species as a target for prevention of age-related loss of muscle mass and function

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As we age, we lose skeletal muscle and this has a major effect on our ability to undertake everyday tasks and, although this can be partly reduced by regular exercise, the mechanisms underlying the loss of muscle remain unknown. One strong possibility is that, as we age, mitochondria (the highly specialised organelle in our muscles that generates the energy we need for movement) start to release increased amounts of highly reactive molecules called free radicals or reactive oxygen species (ROS). These species can damage parts of the muscle cell and prevent them from working properly. We plan to study this possibility on small muscle biopsies taken from the upper thigh muscles under local anaesthetic from volunteers of different ages. Previous techniques have required substantial amounts of tissue to allow isolation of the mitochondria, but we will use an alternative approach in which the muscle biopsies will be split into several small bundles of muscle fibres in which the mitochondria remain in place. These can be studied using techniques that will allow us to assess the amount of ROS released and compare this to the maximum force that the muscle can exert and to the amount of damage that has occurred in the muscle. These studies should allow us to determine the likelihood that increased release of ROS from mitochondria leads to the age-related loss of muscle mass and function. The study will also examine potential therapeutic approaches to reduce the release of ROS from mitochondria by testing the effects of 2 novel compounds that are targeted to the mitochondria. Finally if either of these compounds are found to be promising in their effects, we will undertake a preliminary intervention study in aged mice to determine whether chronic consumption of the drug can prevent the age-related loss of muscle mass and function normally seen in old mice. This is a necessary first step to a potential future intervention study in the elderly.