The role of Heat Shock Factor activation in the age related failure of regeneration in skeletal muscles of old mice.

The applicant is aware of the importance of public engagement in science. Dr McArdle was trained in media presentations as part of her Research into ageing-funded Fellowship and has participated in scientific interviews and discussions with local and national media and charity support groups. As we age, our muscles get smaller and weaker. In addition, muscles of older individuals are more prone to damage and when damaged, do not recover well. This leads to further weakness. This age-related problem has severe implications for older people. Weak muscles will result in an increased risk of falling, which can be fatal in an older person. On a day-to-day basis, muscle weakness leads to an inability of that person to carry out normal every-day tasks. The aim of this study is to understand more comprehensively why old muscles are unable to recover successfully following damage. Muscles of young individuals adapt and train rapidly. This training effect is associated with changes in the pattern of protein content of the muscles. This change in muscle content of a family of proteins, known as Heat Shock Proteins (HSPs) is crucial to the ability of young muscle to repair itself successfully following damage. Our previous work has demonstrated that this ability to produce HSPs does not occur in old muscle. We do not understand fully the role of HSPs and their synthesis during recovery of young and old muscle following damage. Comprehensive understanding of this process will allow us to move closer to developing suitable therapeutic regimes aimed at maintaining the ability of muscles of older individuals to repair successfully following damage and will impact significantly on their Quality of Life.

It has been clearly demonstrated that the ability of muscles of old mice to regenerate following a physiological damage is severely impaired. However, little is known about the status of the muscle at this point of failure. We have demonstrated that this failure is associated with an inability of old muscle to produce HSPs and is corrected by over-expression of a common functioning HSP, HSP70. It is crucial that we understand the cellular characteristics of the muscle at the point in which force generation fails in old mice in comparison with adult wild-type and old HSP70 over-expressor mice. Little is known about the interplay between the the different Heat Shock Transcription Factors (HSFs) in skeletal muscle during regeneration. Studies using mice knocked out for the three factors will provide novel information which will allow us to understand the role of HSPs in the process of regeneration in adult mice and the effect of an inability to transcribe HSPs via the 3 HSFs in the failure of regeneration in muscles of old mice The programme involves a series of integrated studies designed to provide a comprehensive description of the time course of changes in gene transcription and the relationship with the ability to generate force during regeneration in skeletal muscles of adult and old mice. The role of HSF-mediated HSP expression during regeneration will be evaluated using HSP70 over-expressor, HSF1, HSF2 and HSF4 knockout mice. The study will use transgenic technology to provide a comprehensive picture of the role of HSPs in preservation of the ability of old muscles to regenerate. This will be accompanied by a physiological approach to measure muscle function and gene array analysis to characterise the status of the muscle at the point of failure. Thus, the study will use a combination of physiological and immunohistochemical analysis together with gene array analysis. Understanding the interplay between the ability to produce HSPs, transcriptional patterns and the ability of muscle to generate force will be a major advance towards intervention in the age-related deficit in muscle function.