Project Summary While the health-benefits of physical exercise are universally recognized, the underlying molecular mechanisms remain incompletely defined, and might ultimately be exploited for therapeutic benefit. The extensive response triggered by exercise across multiple organs complicates our understanding via classic reductionists approaches. Furthermore, organs do not respond in isolation, and secreted proteins factors involved in inter-organ communication are an important component of tissue adaptation to exercise. Novel proteomic and metabolomic technologies now allow high-throughput, unbiased, and holistic characterization of proteins and metabolites within mammalian tissues. Importantly, the integration of these large-scale technologies have shown promise in identifying important mechanisms of physiological responses. This proposal aims to integrate proteomics and metabolomics data to study the response of multiple organs to exercise. The proposed research will be performed under the mentorship of Steve Carr (proteomics expert, Broad Institute), in collaboration with leading metabolomics and clinical groups through participation within the NIH Molecular Transducers of Physical Activity Consortium (MoTrPAC). Well-established methods from the Carr lab will be implemented to perform deep-scale proteome characterization of tissues from exercised rats, specifically organs known to be involved in disorders caused by physical inactivity and that remain poorly characterized in the context of exercise: heart, liver, and brain. The proteomics data generated will then be integrated with metabolomic data available through MoTrPAC to define protein-dependent mechanisms of metabolic adaptation to exercise. Finally, signaling factors and pathways involved in organ cross-talk in the context of exercise will be defined by measuring protein secreted factors in blood that respond to exercise. This study is expected to provide an unprecedented, detailed view of molecular pathways across an organism and is expected to identify novel forms of protein-dependent metabolic regulation. As this work reveals key mechanistic knowledge about the response of tissues to exercise, it is directly relevant to diseases associated to physical inactivity, such as cardiovascular disease.