NRSA Fellowship for Hettinger: Skeletal Muscle Extracellular Matrix Remodeling Through Cyclic Compressive Loading in Old Rats Recovering from Disuse Atrophy

The control of muscle mass is impaired in older adults, and is exacerbated by periods of muscle disuse common to lengthy hospital stays, immobilization, and physical inactivity. The recovery following disuse atrophy is incomplete in older adults, which contributes to decreased muscle strength. Deficits in muscle strength following disuse atrophy are made worse by accumulating intramuscular connective tissue, i.e. collagen, in older adult skeletal muscle, which is due to a failure in regulating collagen deposition. Lost strength following disuse atrophy in older adults is clinically important due to its tight correlation with morbidity and loss of independence, which combined with the rising population of older adults, equates to a large burden on the United States healthcare system. Therefore, it is critical therapies be made available to regulate excessive collagen deposition in muscles from older adults. Exercise is a commonly used strategy in regulating collagen deposition in muscles from older adults, however may not be practical during the recovery of muscle mass. Massage in the form of cyclic compressive loading may present as a useful alternative in regulating collagen deposition in muscles from older adults, as it is a well-tolerated clinical tool. Using a rat model and our laboratory’s custom-built robotic massage device, we show massage is able to initiate the turnover of collagen in muscles of old rats. However, it is currently unclear how massage initiates turnover of collagen, and further how old age causes a failure in collagen regulation. Therefore, the purpose of this application is to (1) establish massage as a clinical tool to regulate collagen turnover in muscles from old rats undergoing regrowth, and (2) identify mechanisms of collagen regulation during muscle regrowth in old age. Apart from assessing gaps in knowledge regarding interventions for collagen regulation during muscle regrowth in old rats, this proposal is an excellent training platform to accomplish my long-term career goals of becoming an independent scientist. The innovative research plan prepared for this application is overseen by experts in the field of skeletal muscle aging, who have each committed their time in training me to accomplish the goals set out in this application. Combining principles of biomechanics and molecular biology, this is a unique training plan that I stand to significantly benefit from. Lastly, the research to be performed will be carried out at a premiere research institution at the University of Kentucky (UK), as current NIH funding exceeds $85 million. The combination of innovative research, mentorship, and research environment each contribute towards training to become an independent scientist in the field of skeletal muscle aging.