Kavli Affiliate: Michael Miller
| Authors: MoTrPAC Study Group, David Amar, Nicole R. Gay, Pierre M. Jean Beltran, Joshua N. Adkins, Jose J. Almagro Armenteros, Euan Ashley, Julian Avila-Pacheco, Dam Bae, Nasim Bararpour, Charles Burant, Clary Clish, Gary Cutter, Surendra Dasari, Courtney Dennis, Charles R. Evans, Facundo M. Fernández, David Gaul, Yongchao Ge, Robert Gerszten, Laurie J. Goodyear, Zhenxin Hou, Olga Ilkayeva, Anna A. Ivanova, David Jimenez-Morales, Maureen T. Kachman, Hasmik Keshishian, William E. Kraus, Ian R. Lanza, Jun Li, Malene E. Lindholm, Ana C. Lira, Gina M. Many, Shruti Marwaha, Michael E. Miller, Michael J. Muehlbauer, K. Sreekumaran Nair, Venugopalan D. Nair, Archana Natarajan Raja, Christopher Newgard, Eric A. Ortlund, Paul D. Piehowski, David M. Presby, Wei-Jun Qian, Jessica L. Rooney, James A. Sanford, Evan Savage, S tuart C. Sealfon, Gregory R. Smith, Kevin S. Smith, Alec Steep, Cynthia L. Stowe, Yifei Sun, Russell Tracy, Nikolai G. Vetr, Martin J. Walsh, Si Wu, Tiantian Zhang, Bingqing Zhao, Jimmy Zhen, Brent G. Albertson, Mary Anne S. Amper, Ali Tugrul Balci, Marcas Bamman, Elisabeth R. Barton, Bryan Bergman, Daniel Bessesen, Frank Booth, Brian Bouverat, Thomas W. Buford, Tiziana Caputo, Toby L. Chambers, Clarisa Chavez, Maria Chikina, Roxanne Chiu, Michael Cicha, Paul M. Coen, Dan Cooper, Elaine Cornell, Karen P. Dalton, Luis Oliveria De Sousa, Roger Farrar, Kishore Gadde, Nicole Gagne, Bret H. Goodpaster, Marina A. Gritsenko, Kristy Guevara, Fadia Haddad, Joshua R. Hansen, Melissa Harris, Trevor Hastie, Krista M. Hennig, Steven G. Hershman, Andrea Hevener, Michael F. Hirshman, Fang-Chi Hsu, Kim M. Huffman, Chia-Jui Hung, Chelsea Hutchinson-Bunch, Bailey E. Jackson, Catherine Jankowski, Christopher A. Jin, Neil M. Johannsen, Benjamin G. Ke, Wendy M. Kohrt, Kyle S. Kramer, Christiaan Leeuwenburgh, Sarah J. Lessard, Bridget Lester, Xueyun Liu, Ching-ju Lu, Nathan S. Makarewicz, Kristal M. Maner-Smith, DR Mani, Nada Marjanovic, Andrea Marshall, Sandy May, Edward Melanson, Matthew E. Monroe, Ronald J. Moore, Samuel Moore, Kerrie L. Moreau, Charles C. Mundorff, Nicolas Musi, Daniel Nachun, Michael D. Nestor, Robert L. Newton, Jr., Barbara Nicklas, Pasquale Nigro, German Nudelman, Marco Pahor, Cadence Pearce, Vladislav A. Petyuk, Hanna Pincas, Scott Powers, Shlomit Radom-Aizik, Krithika Ramachandran, Megan E. Ramaker, Irene Ramos, Tuomo Rankinen, Alexander (Sasha) Raskind, Blake B. Rasmussen, Eric Ravussin, R. Scott Rector, W. Jack Rejeski, Collyn Richards, Stas Rirak, Jeremy M. Robbins, Aliza B. Rubenstein, Frederique Ruf-Zamojski, Scott Rushing, Tyler J. Sagendorf, Mihir Samdarshi, Irene E. Schauer, Robert Schwartz, Nitish Seenarine, Tanu Soni, Lauren M. Sparks, Christopher Teng, Anna Thalacker-Mercer, John Thyfault, Rob Tibshirani, Scott Trappe, Todd A. Tr appe, Karan Uppal, Sindhu Vangeti, Mital Vasoya, Elena Volpi, Alexandria Vornholt, Michael P. Walkup, John Williams, Ashley Xia, Zhen Yan, Xuechen Yu, Chongzhi Zang, Elena Zaslavsky, Navid Zebarjadi, Sue C. Bodine, Steven Carr, Karyn Esser, Stephen B. Montgomery, Simon Schenk, Michael P. Snyder and Matthew T. Wheeler
| Summary:
Abstract Regular 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 in Rattus norvegicus over 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 the Mef2 family 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/). Highlights Multi-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. Competing Interest Statement S.C.B. has equity in Emmyon, Inc and receives grant funding from Calico Life Sciences. G.R.C. sits on Data and Safety Monitoring Boards for AI Therapeutics, AMO Pharma, Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Horizon Pharmaceuticals, Immunic, Mapi Pharmaceuticals LTD, Merck, Mitsubishi Tanabe Pharma Holdings, Opko Biologics,Prothena Biosciences, Novartis, Regeneron, Sanofi-Aventis, Reata Pharmaceuticals, NHLBI (Protocol Review Committee), University of Texas Southwestern, University of Pennsylvania, Visioneering Technologies, Inc.; serves on Consulting or Advisory Boards for Alexion, Antisense Therapeutics, Biogen, Clinical Trial Solutions LLC, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Merck/Serono, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Protalix Biotherapeutics, Recursion/Cerexis Pharmaceuticals, Regeneron, Roche, SAB Biotherapeutics; and is the President of Pythagoras, Inc. a private consulting company located in Birmingham AL. S.A.C. is a member of the scientific advisory boards of Kymera, PrognomiQ, PTM BioLabs, and Seer. M.P.S. is a cofounder and scientific advisor of Personalis, Qbio, January AI, Filtricine, SensOmics, Protos, Fodsel, Rthm, Marble and scientific advisor of Genapsys, Swaz, Jupiter. S.B.M. is a consultant for BioMarin, MyOme and Tenaya Therapeutics.