Denervation of small numbers of fibres during ageing leads to dysregulation of ROS and functional changes in whole skeletal muscles

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As we age our muscle become smaller and weaker and the reduced muscle function can eventually contribute to frailty and poor quality of life. These changes occur partly because we lose some of the muscle cells (called muscle fibres) as we age, but also the muscle we retain is weak, does not respond well to exercise or training and releases pro-inflammatory compounds that make it more sensitive to damage. It is currently unknown how muscle fibres are lost during ageing, but when these fibres die, the motor nerves that normally control their activity are also lost. We believe that as the muscle fibres and motor nerves die, they release a highly reactive molecule (hydrogen peroxide) that affects the function of the neighbouring muscle fibres and makes them weak, prevents them from responding well to exercise or training and causes them to release pro-inflammatory molecules that make them more sensitive to damage.This possibility will be tested using a mouse model in which a branch of one nerve that innervates a small portion of a muscle in the mouse limb will be cut under anaesthetic to induce denervation of a small number of muscle fibres embedded within a large number of intact innervated fibres. This will not significantly affect muscle function and mobility in the mouse, but will allow us to look at the effects of denervation of a small number of fibres on the neighbouring innervated fibres as a mimic of what occurs during ageing. The effect of this denervation of a small number of fibres on the force generation by the adjacent intact fibres, their ability to adapt following contractions and their release of pro-inflammatory compounds will be examined. The possibility that these changes are mediated by hydrogen peroxide released from the denervated fibres will also be examined.Completion of these studies will provide further information on the mechanisms underlying muscle weakness during ageing and potentially provide indicators of the type of therapeutic interventions that may help preserve muscle function during ageing.