PROJECT SUMMARY Lack of physical activity is central to numerous health problems. Despite this, we have limited understanding of the molecular components which confer the benefit of physical activity and their diverse impacts across tissues with respect to age, sex, genetics, environment and other objective physiologic, morphometric, and metabolic measures. Identifying these molecular signatures offers new opportunities for treatment and therapeutics. The goal of the Molecular Transducers of Physical Activity in Humans Consortium (MoTrPAC) is to assemble a comprehensive map of the molecular changes that occur in response to physical activity and, when possible, relate these changes to the benefits of physical activity. This map will be greatly facilitated by the application of –omics technologies to identify exercise-responsive genes and to relate their benefits across multiple tissues and contexts. Our Stanford Chemical Analysis Site (CAS) is a core component of the MoTrPAC project. Together with Mount Sinai School of Medicine, we form the Genome, Epigenomics and Transcriptomics (GET) team. At Stanford CAS, we have provided molecular data on 7820 samples as part of both human and rat components of MoTrPAC studies. We have further led the development of key quality control and data analysis pipelines to ensure rigor and reproducibility. Our site has also led key consortium manuscripts and engagement efforts from the animal training study. In the final phase of MoTrPAC, we principally aim to provide a genome for every MoTrPAC participant and a transcriptome for every participant sample and facilitate making this data broadly accessible and useful to the research community. Our site will be responsible for the generation of 15784 transcriptomes using RNA-seq. In addition to this effort, we have proposed to generate chromatin accessibility profiles using ATAC-seq on 1190 muscle and PBMC samples and long read transcriptomes using Iso-Seq on 110 muscle samples. The expected benefits of ATAC-seq and Iso-seq efforts will be to enable (1) mapping regulatory changes using chromatin accessibility data, (2) expand profiling of genetic effects using allele-specific measurements and (3) provide complete isoform data for a reference collection of MoTrPAC samples through exercise intervention. Our site provides critical prior expertise and infrastructure to accomplish these production goals and analyses. We have demonstrated expertise for analysis of collected tissues, compliance with MoTrPAC protocols, collaboration with other Chemical Analysis Sites and all other aspects of the consortium, timely data deposition and support of the Bioinformatics Center and expertise in data sharing, enhancement of rigor and reproducibility in Common Fund projects and leading coordinated publication activities. Our PI team also provides MoTrPAC with important cross-consortia expertise to extend its impacts and ensure timely completion. Overall, we are eager to complete the MoTrPAC program as envisioned, overcome remaining obstacles and rapidly share data, tools and analyses to the larger research community.

NARRATIVE While there are many important health benefits of physical activity, how exercise exerts its effects is not fully understood. A more comprehensive understanding of the molecular mechanisms underlying the responses to exercise would significantly impact public health. Continuation of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) will achieve its objective of generating a comprehensive map of the molecular responses to acute exercise and exercise training. with a long-range goal of elucidating the mechanisms by which exercise improves health.