Hospitalizations for disease, injury, and/or surgery in older adults are likely to impair physical mobility and, therefore, the older adults' capacity to be physically active both during hospitalization and beyond. The resulting sedentary lifestyle is likely to be accepted as the ?new normal?, ultimately increasing the risk of skeletal muscle and metabolic dysfunction (e.g. insulin resistance and sarcopenia). Muscle atrophy and insulin resistance are an unfortunate consequence with disuse in older adults. We have observed with our bed rest studies in healthy older adults that in addition to muscle and metabolic changes, we notice increased skeletal muscle inflammation, impaired glucose uptake signaling and an upregulation of enzymes related to de novo ceramide biosynthesis. The accumulation of ceramide, a toxic lipid intermediate, can disrupt glucose homeostasis and impair muscle growth. Metformin treatment has been shown to improve insulin sensitivity and attenuate muscle loss in insulin resistant adults through a mechanism that may involve ceramide synthesis. Metformin used as a preventive strategy to maintain muscle and metabolic health during a period of physical inactivity in older adults has not been investigated. Therefore, I have proposed to conduct a clinical study in older adults to test whether metformin treatment during bed rest will attenuate insulin resistance, muscle loss and accumulation of ceramides. These findings will be foundational in the development of novel treatments, such as metformin, to prevent insulin resistance and muscle atrophy in older adults during disuse periods. In addition to gathering key preliminary data to inform future large scale clinical trials elucidating the muscle protective effects of metformin during disuse, this research project will be linked to specific PhD training experiences, such as the acquisition of new clinical and laboratory skill sets (i.e. coordinating a randomized controlled trial, hyperinsulinemic euglycemic clamps, ceramide analysis methodology) and one-on one interdisciplinary mentoring experiences in aging and skeletal muscle metabolism. Together, this training plan will be a critical stepping stone in the development of my independent research career.
I propose to use metformin therapy in insulin sensitive older adults to prevent muscle loss and insulin resistance during a period of physical inactivity. The long-range goal is to develop a novel, yet safe, pharmacological approach by repurposing metformin to preserve muscle metabolic health in older adults who have become physically inactive as a result of hospitalization, injury, surgery, or illness.
