Endurance Exercise Reshapes the Liver in Males and Females Through Distinct Molecular Routes

Endurance exercise is widely celebrated for its effects on the heart, muscles, and brain, but one of its most consequential targets sits quietly beneath the rib cage. The liver is the body’s central metabolic hub, coordinating cholesterol handling, fat storage, and energy production for the entire organism. New research from the University of Missouri School of Medicine, published in Cell Reports, now shows that when rats undergo sustained endurance training, the molecular rewiring of liver metabolism unfolds along strikingly different paths in males and females. The findings, generated as part of the National Institutes of Health-funded Molecular Transducers of Physical Activity Consortium, or MoTrPAC, suggest that the health benefits of exercise are not delivered through a single universal mechanism but through sex-specific programs of cellular adaptation.

At the heart of the study lies the Krebs cycle, also known as the citric acid cycle, the biochemical engine that operates inside mitochondria and converts nutrients into usable cellular energy. In every aerobic cell, this cyclic series of chemical reactions strips electrons from fuel molecules and hands them to the electron transport chain, ultimately generating ATP, the currency that powers virtually all biological work. The Missouri team discovered that endurance exercise modified this machinery differently depending on the sex of the animal. Female rats responded by producing more of the proteins that constitute the energy cycle, effectively expanding the factory floor. Male rats, by contrast, showed greater chemical modification of their existing proteins, a process known as post-translational remodeling that alters how the same molecular components behave without changing their abundance.

Lead author Scott Rector, a Curators’ Distinguished Professor of Medicine and of Nutrition and Exercise Physiology at Mizzou, framed the distinction as a matter of strategy rather than superiority. Female liver cells, in essence, generated more proteins, while male liver cells changed more of the proteins they already had. He emphasized that these are subtle adjustments in the cellular energy process and that neither sex necessarily ends up with a better modification. The observation is significant because it demonstrates that even a deeply conserved pathway like the Krebs cycle can be tuned by exercise in ways that diverge between the sexes, hinting at why metabolic diseases sometimes present and progress differently in men and women.

Despite the divergent molecular routes, the study found that the destination was beneficial for both sexes. Exercise training improved liver health across the board, with measurable reductions in liver fat, improved cholesterol use and disposal, and fewer markers of fibrosis, the accumulation of scar tissue that typically accompanies liver injury or chronic disease. Fibrosis is a critical clinical indicator because progressive scarring can push a fatty liver toward cirrhosis or cancer, outcomes that can be fatal. The fact that both males and females showed these improvements, even while achieving them through different molecular means, underscores the robustness of exercise as a therapeutic intervention for the liver.

One sex-specific difference did emerge at the whole-body level. Male rats appeared to expel more cholesterol from the body than females did, suggesting that the male liver prioritizes export of this lipid, while females may handle cholesterol through other pathways. Cholesterol disposal is a central concern in metabolic health because excess cholesterol contributes to cardiovascular disease and is implicated in the progression of fatty liver conditions. The researchers note that why these different adaptations occur remains unclear, and Rector’s team plans to investigate how the observed changes in the cellular energy cycle might ripple outward to shape whole-body metabolism, the integrated process by which the body creates and uses energy.

The clinical stakes of this work are considerable. The findings point toward metabolic dysfunction-associated steatotic liver disease, or MASLD, the modern name for what was previously called nonalcoholic fatty liver disease. MASLD is the most common chronic liver condition, and its prevalence is climbing in lockstep with rising rates of obesity worldwide. In its most severe forms, MASLD can progress to cirrhosis or liver cancer, both of which can be fatal. Because current treatments are limited and largely rely on lifestyle change, understanding precisely how exercise remodels liver metabolism could enable more precise and personalized interventions, matched to a patient’s sex and metabolic profile rather than applied as a one-size-fits-all prescription.

Methodologically, the study exemplifies the multi-omics approach that defines the MoTrPAC initiative, one of the largest concerted efforts in biology to map the molecular effects of exercise across tissues. Rather than measuring a single molecule or pathway, multi-omics studies integrate data on proteins, their chemical modifications, metabolites, and other molecular layers over time, capturing what the authors describe as temporal and sexually dimorphic remodeling. This means the researchers tracked not only which molecules changed but when they changed during the training period, revealing a dynamic choreography of adaptation rather than a static before-and-after snapshot. Such temporal resolution is essential for distinguishing early signaling events from the stable structural changes that ultimately define a trained liver.

The choice of an experimental animal model is also central to the study’s design. By controlling diet, exercise intensity, and environment in rats, the researchers could isolate the effects of endurance training itself, something that is extraordinarily difficult in human studies where adherence, diet, and genetics introduce confounding variables. The trade-off is that findings in rats must ultimately be validated in people, but the conservation of core metabolic pathways between rodents and humans makes the liver an especially promising tissue for translation. The Krebs cycle, mitochondrial protein remodeling, and cholesterol transport all operate on principles shared across mammals, giving the results a plausible path toward clinical relevance.

The research was a collaborative effort spanning institutions. In addition to Rector, Mizzou study authors include Taylor Kelty, a research assistant professor at NextGen Precision Health, and John Thyfault, professor of cell biology and physiology at the University of Kansas Medical Center, who served as co-corresponding author. Rector’s laboratory is a member of MoTrPAC, which is supported by the NIH Common Fund through cooperative agreements managed by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Arthritis and Musculoskeletal Diseases, and the National Institute on Aging. The authors declared no competing interests, and the paper appeared in Cell Reports under the title describing endurance exercise as eliciting temporal and sexually dimorphic multi-omics remodeling of liver metabolism.

For the public, the takeaway is both simple and nuanced. Consistent endurance exercise demonstrably improves the metabolic machinery of the liver in both sexes, reducing fat accumulation, improving cholesterol handling, and limiting scarring. But the cellular language in which those improvements are written differs between males and females, with females building more of the energy-producing apparatus and males chemically retuning what they already possess. As researchers continue to decode these sex-specific molecular transducers of physical activity, the long-term promise is a future in which exercise prescriptions and therapies for liver disease are tailored not just to how much a person moves, but to the distinct biology their body uses to respond.

Subject of Research: Sex-specific molecular remodeling of liver metabolism by endurance exercise in a rat model

Article Title: Exercise rewires liver metabolism differently based on sex

Article References: Exercise rewires liver metabolism differently based on sex. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: endurance exercise, liver metabolism, Krebs cycle, mitochondria, sex differences, MASLD, fatty liver disease, cholesterol, fibrosis, MoTrPAC, multi-omics, Cell Reports