Temporal dynamics of the multi-omic response to endurance exercise training across tissues
Authors:   MoTrPAC Study Group, Amar David , Gay Nicole R. , Jean Beltran Pierre M. , Adkins Joshua N. , Almagro Armenteros Jose J. , Ashley Euan , Avila-Pacheco Julian , Bae Dam , Bararpour Nasim , Burant Charles , Clish Clary , Cutter Gary , Dasari Surendra , Dennis Courtney , Evans Charles R. , Fernández Facundo M. , Gaul David , Ge Yongchao , Gerszten Robert , Goodyear Laurie J. , Hou Zhenxin , Ilkayeva Olga , Ivanova Anna A. , Jimenez-Morales David , Kachman Maureen T. , Keshishian Hasmik , Kraus William E. , Lanza Ian R. , Li Jun , Lindholm Malene E. , Lira Ana C. , Many Gina M. , Marwaha Shruti , Miller Michael E. , Muehlbauer Michael J. , Nair K. Sreekumaran , Nair Venugopalan D. , Natarajan Raja Archana , Newgard Christopher , Ortlund Eric A. , Piehowski Paul D. , Presby David M. , Qian Wei-Jun , Rooney Jessica L. , Sanford James A. , Savage Evan , Sealfon Stuart C. , Smith Gregory R. , Smith Kevin S. , Steep Alec , Stowe Cynthia L. , Sun Yifei , Tracy Russell , Vetr Nikolai G. , Walsh Martin J. , Wu Si , Zhang Tiantian , Zhao Bingqing , Zhen Jimmy , Albertson Brent G. , Amper Mary Anne S. , Balci Ali Tugrul , Bamman Marcas , Barton Elisabeth R. , Bergman Bryan , Bessesen Daniel , Booth Frank , Bouverat Brian , Buford Thomas W. , Caputo Tiziana , Chambers Toby L. , Chavez Clarisa , Chikina Maria , Chiu Roxanne , Cicha Michael , Coen Paul M. , Cooper Dan , Cornell Elaine , Dalton Karen P. , De Sousa Luis Oliveria , Farrar Roger , Gadde Kishore , Gagne Nicole , Goodpaster Bret H. , Gritsenko Marina A. , Guevara Kristy , Haddad Fadia , Hansen Joshua R. , Harris Melissa , Hastie Trevor , Hennig Krista M. , Hershman Steven G. , Hevener Andrea , Hirshman Michael F. , Hsu Fang-Chi , Huffman Kim M. , Hung Chia-Jui , Hutchinson-Bunch Chelsea , Jackson Bailey E. , Jankowski Catherine , Jin Christopher A. , Johannsen Neil M. , Ke Benjamin G. , Kohrt Wendy M. , Kramer Kyle S. , Leeuwenburgh Christiaan , Lessard Sarah J. , Lester Bridget , Liu Xueyun , Lu Ching-ju , Makarewicz Nathan S. , Maner-Smith Kristal M. , Mani DR , Marjanovic Nada , Marshall Andrea , May Sandy , Melanson Edward , Monroe Matthew E. , Moore Ronald J. , Moore Samuel , Moreau Kerrie L. , Mundorff Charles C. , Musi Nicolas , Nachun Daniel , Nestor Michael D. , Newton Robert L. , Nicklas Barbara , Nigro Pasquale , Nudelman German , Pahor Marco , Pearce Cadence , Petyuk Vladislav A. , Pincas Hanna , Powers Scott , Radom-Aizik Shlomit , Ramachandran Krithika , Ramaker Megan E. , Ramos Irene , Rankinen Tuomo , Raskind Alexander (Sasha) , Rasmussen Blake B. , Ravussin Eric , Rector R. Scott , Rejeski W. Jack , Richards Collyn , Rirak Stas , Robbins Jeremy M. , Rubenstein Aliza B. , Ruf-Zamojski Frederique , Rushing Scott , Sagendorf Tyler J. , Samdarshi Mihir , Schauer Irene E. , Schwartz Robert , Seenarine Nitish , Soni Tanu , Sparks Lauren M. , Teng Christopher , Thalacker-Mercer Anna , Thyfault John , Tibshirani Rob , Trappe Scott , Trappe Todd A. , Uppal Karan , Vangeti Sindhu , Vasoya Mital , Volpi Elena , Vornholt Alexandria , Walkup Michael P. , Williams John , Xia Ashley , Yan Zhen , Yu Xuechen , Zang Chongzhi , Zaslavsky Elena , Zebarjadi Navid , Bodine Sue C. , Carr Steven , Esser Karyn , Montgomery Stephen B. , Schenk Simon , Snyder Michael P. , Wheeler Matthew T. 
Published: September 2022

AbstractRegular exercise promotes whole-body health and prevents disease, yet the underlying molecular mechanisms throughout a whole organism are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome, and immunome in whole blood, plasma, and 18 solid tissues inRattus norvegicusover 8 weeks of endurance exercise training. The resulting data compendium encompasses 9466 assays across 19 tissues, 25 molecular platforms, and 4 training time points in young adult male and female rats. We identified thousands of shared and tissue- and sex-specific molecular alterations. Temporal multi-omic and multi-tissue analyses demonstrated distinct patterns of tissue remodeling, with widespread regulation of immune, metabolism, heat shock stress response, and mitochondrial pathways. These patterns provide biological insights into the adaptive responses to endurance training over time. For example, exercise training induced heart remodeling via altered activity of theMef2family of transcription factors and tyrosine kinases. Translational analyses revealed changes that are consistent with human endurance training data and negatively correlated with disease, including increased phospholipids and decreased triacylglycerols in the liver. Sex differences in training adaptation were widespread, including those in the brain, adrenal gland, lung, and adipose tissue. Integrative analyses generated novel hypotheses of disease relevance, including candidate mechanisms that link training adaptation to non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health, and tissue injury and recovery. The data and analysis results presented in this study will serve as valuable resources for the broader community and are provided in an easily accessible public repository (https://motrpac-data.org/).HighlightsMulti-tissue resource identifies 35,439 analytes regulated by endurance exercise training at 5% FDR across 211 combinations of tissues and molecular platforms.Interpretation of systemic and tissue-specific molecular adaptations produced hypotheses to help describe the health benefits induced by exercise.Robust sex-specific responses to endurance exercise training are observed across multiple organs at the molecular level.Deep multi-omic profiling of six tissues defines regulatory signals for tissue adaptation to endurance exercise training.All data are available in a public repository, and processed data, analysis results, and code to reproduce major analyses are additionally available in convenient R packages.