Targeting Intramuscular Adipose Quality in Aging - PROJECT SUMMARY Typical aging features progressive muscle weakness and loss of physical ability which impacts quality of life for millions of Americans. Beyond loss of lean muscle mass, muscle weakness and physical dysfunction are strongly associated with increasing ectopic adipose within the muscle boundary. The mechanism behind this association is not clear, but evidence suggests that this intramuscular adipose tissue (IMAT) secretes signals that locally impair muscle contraction. Paralleling work in visceral adipose tissue, we propose that IMAT secreted signals are dynamic rather than static, and as such are influenced by the local and systemic environment. More specifically, it is our central hypothesis that, like visceral adipose, IMAT has reduced quality with age due to senescent changes in cellular composition and that these senescent features are modifiable by exercise or a combination of exercise and pharmacology, to improve signaling. To address our hypothesis we will complete two parallel aims, one in people and one in mice. Both aims will have two age groups (~30% and ~80% of lifespan) and will evaluate the effect of aging and a 12 week progressive resistance exercise program on IMAT senescence. The primary objective of the first aim is to assess IMAT senescent and signaling changes with age and exercise. To date, IMAT changes with age and exercise have only been assessed with non-invasive imaging which has limited our ability to target cellular functions. The primary objective of the second aim is to determine whether age- and exercise-responsive human IMAT features are present in a mouse IMAT model. Rodents develop little IMAT with age and thus there are few studies of IMAT in mice. We will examine the suitability of a toxin-induced IMAT model in mice to study the intersection of aging and exercise on IMAT. The long-term goal of this work is to develop a feed-forward system where therapeutic targets are identified from human tissue and mechanistically assessed in mice. Toward that goal, these studies will improve our understanding of the basic biology of aging IMAT, the plasticity of IMAT signaling and the translational utility of a toxin-induced IMAT model.
