First Steps Toward a Whole-Body Map of Molecular Responses to Exercise

A first major paper

MoTrPAC researchers nationwide contributed to a May 2, 2024, study in the journal Nature. This first major paper to come out of the consortium provides the first whole-organism map of molecular responses to endurance exercise training. The experiment’s model organism was the rat. Male and female rats of the same species ran on motorized treadmills for 1-, 2-, 4-, and 8-week periods. For controls, researchers used sedentary, untrained rats, matched for sex with their exercising counterparts. Within 48 hours of each training interval, researchers collected samples of whole blood, plasma, and 18 solid tissues and dispersed them to omics centers like PNNL for intensive analysis.

Of the numerous samples, said Adkins, “We want to understand the integration of organ systems.” Molecular responses in the body to endurance training are system-wide, say authors of the Nature paper—a conclusion confirmed by integrating tissue samples in a range of omics analyses.

Other results were finer tuned. Exercise enhances liver health and metabolism, for instance. It also remodels and strengthens the structure of the heart, improves pathways related to gut integrity (gut health is linked to inflammation throughout the body), enriches immune pathways, and reduces inflammation in the lungs and small intestine. Importantly, the authors relate, the sex differences observed in training responses highlight how important it is to include both sexes in exercise research.

The rat–human problem

Translating rat data into conclusions relevant to humans is challenging. However, rats are the preferred animal model because rat–human skeletal muscle and organ system signaling patterns are similar. So are exercise-induced glucose metabolism and cardiac responses. In addition, the large tissue masses of rats provide better samples than mice for multiomics analysis.

“These data will help us bring knowledge from the rat into the human sphere,” said Adkins.

To help close the rat–human data gap, the MoTrPAC consortium has an exercise-response experiment underway that records molecular responses to endurance training and resistance training across a cohort of 2,000 adult human volunteers.

Insights, with more on the way

The recent Nature paper provides what Adkins called “a landscape view” of multi-center national MoTrPAC research. At the same time, other studies in progress are taking narrower and more detailed views of consortium data. PNNL’s Sanford is part of a research team showing how multiomics help identify key gene regulatory programs that come into play during exercise. The Sanford team is looking at thousands of observed molecular alterations. They included how exercise regulates gene expression related to mitochondrial changes, heat shock responses, immune regulation, and other molecular processes.

Sanford has also joined PNNL biostructure and function biochemist Gina Many and PNNL data scientist Tyler Sagendorf in an analysis of the running-rats data to investigate sexual dimorphism in white adipose tissue responses. White adipose is a storage and secretory organ system linked to the development of obesity, cardiovascular disease, Type 2 diabetes, cancer, and other conditions. This fat type also has important effects on the immune system and other biological processes that maintain systemic health.

So far, the analysis seems to demonstrate that in rats there are “profound” differences in white adipose tissue response between the sexes. While physical training benefits rats of both sexes, only male rats respond to exercise by losing white adipose tissue. In female rats, exercise prevents them from gaining fat mass.

Such narrowly focused investigations use the MoTrPAC dataset to look for insights on how exercise affects individual tissues or specific biological processes.

One MoTrPAC investigation underway, for instance, looks at how exercise affects gene transcription. That’s the process of copying information from a strand of DNA onto a molecule called messenger RNA (mRNA), which relays genetic information to the areas of cells where proteins are made. Another example of research in progress deals with the impact of exercise on mitochondrial response. Mitochondria, present in mammalian cells, regulate energy production and stress response.

Every smaller study based on separate facets of MoTrPAC data, said Adkins, “is one piece of a greater vision.” That vision is the consortium’s: to map the body’s molecular changes after exercise.