Grant: Operating Grant

The muscles that we use for movements and locomotion are highly adaptable. For example, muscles can undergo enlargement (hypertrophy) in response to exercise, and they can shrink, or atrophy, when they are not used for prolonged periods of time. This adaptability has been studied for many years, but recently it has become known that a cellular process known as "autophagy" may be very important in the adaptive process. Autophagy, or "self-eating", is a series of events within the cell that leads to the breakdown of damaged cellular components, like internal organelles. We are particularly interested in the mitochondria within cells, because they are the organelles that generate energy for cell survival. Mitochondrial number within muscle cells is markedly reduced, and the remaining organelles do not function well, during conditions of chronic muscle disuse, leading to increased muscle fatigue and the production of damaging molecules called "reactive oxygen species", or ROS. An increase in the formation of ROS can lead to cell death, and to the degradation of DNA. The role of autophagy appears to be to remove, or digest, these damaged organelles, in order to minimize the consequences to the cell of having mitochondria that function poorly. The importance of autophagy has only recently been recognized in muscle. Therefore, the processes involved in the regulation of autophagy are still poorly understood. This is important for our understanding of muscle health, and our comprehension of how muscle adapts to exercise, or particularly the lack of exercise. The purpose of this research proposal is to clearly identify some of the important regulatory features of autophagy in our muscles, using animal and cell culture models of chronic muscle disuse.