Endurance exercise elicits temporal and sexual dimorphic multi-omics remodeling of liver metabolism revealed by MoTrPAC

Taylor J Kelty; Edziu Franczak; Nicole R Gay; Gina M Many; Tyler J Sagendorf; James A Sanford; Zhenxin Hou; David A Gaul; Facundo M Fernández; Michaella Rekowski; Charles F Burant; Andrea L Hevener; Joshua N Adkins; Sue Bodine; Malene E Lindholm; Eric A Ortlund; Simon Schenk; John P Thyfault; R Scott Rector; MoTrPAC study group

doi:10.1016/j.celrep.2026.117416

Endurance exercise elicits temporal and sexual dimorphic multi-omics remodeling of liver metabolism revealed by MoTrPAC

Cell Rep. 2026 Jun 23;45(6):117416. doi: 10.1016/j.celrep.2026.117416. Epub 2026 Jun 8.

Authors

Taylor J Kelty¹, Edziu Franczak², Nicole R Gay³, Gina M Many⁴, Tyler J Sagendorf⁴, James A Sanford⁴, Zhenxin Hou⁵, David A Gaul⁶, Facundo M Fernández⁶, Michaella Rekowski⁷, Charles F Burant⁸, Andrea L Hevener⁹, Joshua N Adkins⁴, Sue Bodine¹⁰, Malene E Lindholm¹¹, Eric A Ortlund⁵, Simon Schenk¹², John P Thyfault¹³, R Scott Rector¹⁴; MoTrPAC study group

Collaborators

MoTrPAC study group:
Brent G Albertson, Mary Anne S Amper, Carter Asef, Matthew Babcock, Dam Bae, Marcas M Bamman, Bryan C Bergman, Daniel H Bessesen, Thomas W Buford, Steven Carr, Chih-Yu Chen, Zachary S Clayton, Gary R Cutter, Yongchao Ge, Laurie J Goodyear, Kristy Guevara, Xueyun Gulbin, Michael F Hirshman, Catherine M Jankowski, Pierre M Jean Beltran, Hasmik Keshishian, Wendy M Kohrt, Sarah J Lessard, Bridget Lester, Ana K Lira, Nathan S Makarewicz, Kristal M Maner-Smith, Nada Marjanovic, Edward L Melanson, Michael E Miller, Samuel G Moore, Kerrie L Moreau, Charles C Mundorff, Venugopalan D Nair, German Nudelman, Nora-Lovette Okwara, Paul D Piehowski, Wei-Jun Qian, Blake B Rasmussen, Stas Rirak, Irene E Schauer, Nitish Seenarine, Cynthia L Stowe, Yifei Sun, Scott Trappe, Todd A Trappe, Mital Vasoya, Alexandria Vornholt, Michael P Walkup, Ashley Xia, Xuechen Yu

Affiliations

¹ NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA.
² Departments of Cell Biology and Physiology and Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA; Kansas Center for Metabolism and Obesity Research and KU Diabetes Institute, University of Kansas Medical Center, Kansas City, KS, USA.
³ Department of Genetics, Stanford University, Stanford, CA, USA.
⁴ Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
⁵ Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
⁶ School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA.
⁷ Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA; Mass Spectrometry and Proteomics Core Facility, University of Kansas Medical Center, Kansas City, KS, USA.
⁸ Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁹ Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, University of California, Los Angeles, CA, USA.
¹⁰ Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
¹¹ Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
¹² Department of Orthopedic Surgery, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
¹³ Departments of Cell Biology and Physiology and Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA; Kansas Center for Metabolism and Obesity Research and KU Diabetes Institute, University of Kansas Medical Center, Kansas City, KS, USA; Research Service, Kansas City VA Medical Center, Kansas City, MO, USA. Electronic address: jthyfault@kumc.edu.
¹⁴ NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO, USA; Research Service, Harry S. Truman Memorial VA Medical Center, Columbia, MO, USA. Electronic address: rectors@health.missouri.edu.

PMID: 42258354
DOI: 10.1016/j.celrep.2026.117416

Abstract

The mechanisms by which exercise modulates liver metabolism are poorly understood. Leveraging data from molecular transducers of physical activity consortium (MoTrPAC), we analyzed liver adaptations across 1, 2, 4, and 8 weeks of exercise in male and female rats using multi-omics approaches. Female livers displayed a progressive increase in oxidative phosphorylation (OXPHOS) protein complexes, while male livers showed an increased acetylation of OXPHOS, tricarboxylic acid cycle, and fatty acid oxidation enzymes. Mechanistic examination revealed that these sex-specific acetylation events are partially mediated by carnitine acetyltransferase. Exercise enhanced liver cholesterol and bile acid synthesis, reducing liver lipid metabolites in males after 8 weeks of exercise. Male rats had higher fecal cholesterol and cholic acid levels, indicating a sex-specific mechanism of lipid excretion with exercise. Eight weeks of training reduced markers related to hepatic stellate cell activation and fibrosis in both sexes. This study highlights the sexual dimorphic and temporal molecular signatures by which exercise modulates liver metabolism to provide hepatoprotective effects.

Keywords: CP: metabolism; CrAT; bile acids; endurance exercise; lipids; liver; metabolism; mitochondria; omics.

MeSH terms

Acetylation
Animals
Bile Acids and Salts / metabolism
Cholesterol / metabolism
Female
Lipid Metabolism
Liver* / metabolism
Male
Multiomics
Oxidative Phosphorylation
Physical Conditioning, Animal*
Rats
Sex Characteristics*

Substances

Bile Acids and Salts
Cholesterol