First steps toward a whole-body map of molecular responses to exercise

Research definitively confirms that muscle activity and calorie burning slows disease progression, improves cognitive function, boosts the immune system, and lowers all-cause mortality rates.

Scientists are now looking further into the effects of exercise in humans and other mammals by investigating the impacts of exercise at the molecular level. They aim to discover, at the smallest scales, the impacts of exercise and better understand how the body works in states of health and disease.

Molecules are groups of atoms. They represent the smallest unit of a chemical compound that can participate in a chemical reaction. These chemical reactions in proteins, carbohydrates, lipids (fats) and nucleic acids – the “omics” (cellular components) that control the inner workings of each organ system.

Exercise appears to change these molecular workhorses in poorly understood ways. The identification of these changes, however, holds the promise of clinical benefits for all humans, regardless of age, sex, body composition, or fitness level.

The genesis of MoTrPAC

In late 2016, to learn more about exercise-induced changes at the molecular level, the National Institutes of Health Common Fund began supporting expanded research to map the finer details of how exercise helps maintain healthy tissues and organ systems. This led to the establishment of a national collaborative expert group called the Molecular Transductors of Physical Activity Consortium (MoTrPAC).

From the beginning, the Pacific Northwest National Laboratory (PNNL), under the direction of biochemists Josh Adkins and Wei-Jun Qian, has been among MoTrPAC’s national centers of expertise in animal and human exercise, biomolecular analysis, and bioinformatics.

The consortium’s biomolecular analysis centers use an omics approach to analyze genes, proteins or other biomolecules at the whole-body level. Ultimately, the goal of MoTrPAC is to create a molecular map of exercise responses in both human and animal models. From muscle to molecule, this map would help reveal how exercise affects health.

“The ability to see broad molecular responses across organs in the body is particularly intriguing,” said Qian of molecular mapping. “This knowledge can be a strong motivating factor to exercise.”

An emphasis on proteomics

PNNL’s primary role at MoTrPAC is to investigate exercise-induced changes in proteins and post-translational modifications (PTMs). Proteins are made of chains of amino acids that fold into three-dimensional structures and then regulate the structure and function of tissues and organs. PTMs are processing events that alter protein functions by chemically modifying specific amino acids within a given protein. The study of changes in all detectable proteins and their PTMs in a sample is called proteomics.

“We have been instrumental in the design of the consortium study from the beginning, with an emphasis on proteomics,” Adkins said. He recognized a critical partner: Steven Carr and his proteomics group at the Broad Institute, a research center run by Harvard University and the Massachusetts Institute of Technology.

A mapping challenge

In an overview of 2020 in the magazine cell, Adkins and PNNL biomedical scientist James Sanford joined with other co-authors to describe molecular “cross-talk,” a kind of chemical telegraph triggered by exercise between a variety of tissues. The study also highlighted the importance of mapping these molecular exchanges.

The cell The paper also introduced the idea of ​​a public MoTrPAC dataset to help find the hidden mechanisms behind the benefits of exercise. Now it is growing and growing. One of the lead analysts on the data set is PNNL chemist Paul Piehowski.

For Adkins, Qian and others on PNNL’s MoTrPAC team, proteomics research depends on instruments at the Environmental Molecular Sciences Laboratory (EMSL), a user facility of the Department of Energy’s Office of Science located on the PNNL campus. EMSL’s capabilities include a number of high-end orbital mass spectrometers. They produce assays that help identify and quantify proteins and other molecules in a variety of tissue types and samples.

MoTrPAC “has a huge reach,” Adkins said. “PNNL’s scale of operation allows us to do something of this size with very high quality and high operational reproducibility.” He called the PNNL-EMSL paper in MoTrPAC “a tour de force for a proteomic study. Few on this scale have been done before.”

An important first role

MoTrPAC researchers across the country contributed to a May 2, 2024, study in the journal Nature. This first major paper from the consortium provides the first map of whole-body molecular responses to resistance exercise training.

The model organism of the experiment was the rat. Male and female rats of the same species ran on motorized treadmills for periods of 1, 2, 4, and 8 weeks. For controls, the researchers used sedentary, untrained rats, matched for sex with their exercising counterparts.

Within 48 hours of each training interval, the researchers collected whole blood, plasma, and 18 solid tissue samples and dispersed them to omics centers such as PNNL for intensive analysis.

From the many samples, Adkins said, “we want to understand the integration of organ systems.” The body’s molecular responses to resistance training are system-wide, say the authors of the Nature paper: a conclusion confirmed by integrating tissue samples in a series of omics analyses.

Other results were more refined. Exercise improves liver health and metabolism, for example. It also remodels and strengthens the structure of the heart, improves pathways related to gut integrity (gut health is related to inflammation throughout the body), enriches immune pathways, and reduces inflammation in the lungs and small intestine. Importantly, the authors report, the gender differences observed in training responses highlight the importance of including both sexes in exercise research.

The rat-man problem

Translating rat data into conclusions relevant to humans is a challenge. However, rats are the preferred animal model because the signaling patterns of human skeletal muscle and the rat-human organ system 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 multiomic analysis.

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

To help close the data gap between rat and man, the MoTrPAC consortium is running an exercise response experiment that records molecular responses to resistance training and resistance training in a cohort of 2,000 adult human volunteers.

Insights, with more on the way

The recent Nature The paper provides what Adkins called “a view of the landscape” of MoTrPAC’s multicenter national research. At the same time, other ongoing studies are taking more limited and detailed views of the consortium data. PNNL’s Sanford is part of a research team showing how multiomics helps identify key gene regulatory programs that come into play during exercise.

Sanford’s team is analyzing 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 data from running rats to investigate sex dimorphism in white adipose tissue responses.

White adipose is a secretory and storage organ system linked to the development of obesity, cardiovascular disease, type 2 diabetes, cancer and other conditions. This type of fat also has important effects on the immune system and other biological processes that maintain systemic health.

So far, the analysis appears to show that in rats there are “profound” differences in the response of white adipose tissue between the sexes. Although physical training benefits rats of both sexes, only males respond to exercise by losing white adipose tissue. In female rats, exercise prevents them from gaining too much fat.

These highly focused investigations use the MoTrPAC dataset to search for information on how exercise affects individual tissues or specific biological processes.

An ongoing MoTrPAC investigation, for example, examines how exercise affects gene transcription. This is the process of copying information from a strand of DNA into a molecule called messenger RNA (mRNA), which carries the genetic information to the areas of the cells where proteins are made. Another example of ongoing research deals with the impact of exercise on the mitochondrial response. Mitochondria, present in mammalian cells, regulate energy production and the response to stress.

Each smaller study based on separate facets of the MoTrPAC data, Adkins said, “is a piece of a bigger picture.” This vision is that of the consortium: to map the molecular changes in the body after exercise.