Site-specific failure of redox homeostasis as a cause of age-related loss of skeletal muscle mass and function

As we age, our muscles become smaller and weaker, are more susceptible to damage following exercise and recovery from damage is severely impaired. Loss of muscle leads to a severe reduction in quality of life for the elderly due to increased need for assistance and residential care and increased risk of hypothermia and incontinence. We plan to investigate in mice how this age-related loss of muscle occurs as a means of eventually developing ways of preventing these changes in later life in people. A number of studies have indicated that highly reactive substances called free radicals are involved in causing ageing-related changes in many tissues, but the way that they lead to loss of muscle is unclear. We will investigate the possibility that these free radicals react with some key proteins in the muscle that regulate the way that muscle adapts to everyday tasks to prevent damage to the muscle. Our investigations will characterise the processes that occur during ageing and identify potential ways in which we might modify the muscles of old mice (and potentially those of old people) to help restore the ability to respond to everyday use and hence maintain their muscle mass.

Age-related loss of muscle mass and function is a major cause of frailty and loss of independence in the elderly. The mechanisms underlying the loss of muscle function during ageing are not understood although increased oxidation of cellular components by reactive oxygen species (ROS) and a failure of skeletal muscle from old organisms to adapt to increased ROS both appear to play important roles in the pathophysiology of age-related loss of muscle. Cellular thiols are readily oxidised by ROS and play a role in protection of cells against oxidative damage, but this oxidation also leads to a change in the thiol/disulphide ratios which are important in regulation of the activity of some key transcription factors (such as NFkB and AP-1) within the muscle fibre. ROS generated as part of normal physiological processes such as contractile activity in muscle appear to oxidise cytosolic thiols and stimulate adaptive responses. It is hypothesised that ageing is associated with abberant ROS generation at specific sub-cellular sites, excessive site-specific thiol oxidation and a failure of adaptations to physiological processes in skeletal muscle. This project will test this hypothesis by using new analytical approaches that permit analyses of specific ROS (superoxide, hydrogen peroxide, NO) in mitochondria and cytosol of isolated single mature skeletal muscle fibres and analyses of reduced and oxidised thioredoxin (TRx) 1 in nuclei and cytosol and reduced and oxidised Trx2 in mitochondria of skeletal muscle fibres. Specific interventions to attempt to correct sub-cellular deficit(s) in thiol homeostasis by overexpression of TRx1 or TRx2 or by enhancement of cellular thiols (by lipoic acid supplementation) will then be used to restore redox signalling processes and overcome the inability to adapt to physiological stressors that normally characterises the muscle fibres from old mice. It is anticipated that these studies will indicate novel approaches to preservation of muscle function and mass during ageing with potential influences on quality of life of the elderly.