Mechanisms of Anabolic Resistance in Older Humans

Our preliminary data suggest that inflamed adipose tissue may contribute to blunted exercise response in skeletal muscle of older adults. The objective of this project is to evaluate a hypothesis that inflamed adipose secretes factors that activate inflammatory cascades in skeletal muscle, which may interfere with exercise- responsive molecular pathways and contribute to dysfunctional muscle phenotypes with aging. Aim 1 will determine how adipose tissue influences skeletal muscle function and anabolic response to exercise in older adults. A combination of in vivo imaging and molecular phenotyping will be used to characterize abdominal adipose tissue (AAT) and intermuscular adipose tissue (IMAT) in young and older adults. Molecular response to acute exercise will be determined from protein synthesis rates, exercise- responsive mRNAs, and activation of signaling proteins in muscle. This aim will evaluate the relationship between adipose tissue inflammation and skeletal muscle phenotypes and function in older adults. Aim 2 will identify the molecular pathways by which AAT and IMAT influence muscle phenotype and exercise response in older adults. Primary muscle cultures and adipose conditioned media (AAT, IMAT) will be generated from tissue collected in aim 1. Myotubes will be exposed to adipose explant media or serum from inflamed or non-inflamed donors to evaluate their influence on molecular phenotype and response to exercise mimetics in vitro. Chemical inhibition of canonical inflammatory pathways in muscle will be used to determine their role in attenuating molecular response to exercise. Molecular profiling of conditioned media and serum will be used to identify candidate molecules for subsequent experiments to assess their individual influence on canonical exercise response pathways. The contribution of the proposed research is expected to be in the form of new insights into the paracrine/endocrine influence of adipose tissue on skeletal muscle responsiveness to exercise in older adults. The knowledge gained in the proposed study will have a positive impact because anabolic resistance is common in older adults and believed to contribute to sarcopenia, frailty, and loss of independence. This work will provide insight into the link between adipose tissue dysfunction and skeletal muscle biology in aging with a particular focus on distinct adipose tissue pools that are likely to have unique endocrine or paracrine influence on skeletal muscle. We will also gain new knowledge of how targeting inflammatory pathways in adipose tissue and skeletal muscle may enhance acute adaptations to exercise in older adults.