Lay Abstract Older adults are prone to periods of muscle disuse (surgery, illness, injury) resulting in muscle atrophy, weakness and insulin resistance. Moreover, muscle and metabolic recovery following a disuse event is impaired in older adults thereby placing this vulnerable population at risk for falls, fractures, hospitalizations and development of metabolic disorders such as type 2 diabetes mellitus. A unique process that may impair muscle regrowth and glucose homeostasis during recovery from physical inactivity is inflammation-mediated accumulation of the lipid intermediate, ceramide, and reduced mitochondrial function (defined as H2O2 emission and decline in mitochondrial biogenesis). Metformin, a widely used treatment in adults with T2D, has multi-organ effects including skeletal muscle, and is currently being explored as a remedy to offset age-related diseases. Interestingly, metabolic disruption and lipid accumulation is reversed in conditions of obesity when metformin is combined with the branched-chain amino acid, leucine, (a known stimulant of muscle protein synthesis) but it is not known if this therapeutic combination can amplify muscle and metabolic recovery following disuse in aging. Therefore, the goal of this project is to re-purpose metformin and combine it with leucine to enhance muscle size and glucose regulation in old mice during recovery from disuse (i.e., hindlimb unloading). This information will be critical in the development new therapeutics to timely and fully reverse muscle atrophy, weakness and metabolic decline in older adults following disuse.
We propose to use metformin and leucine to optimize muscle and metabolic recovery in aging with an established mouse model of disuse and recovery. Our long-range goal is to develop a novel, yet safe, pharmacological approach by repurposing metformin (and in combination with leucine) to preserve muscle health in older adults who have slow and impaired muscle and metabolic recovery as a result of hospitalization, injury, surgery, or illness.!