Characterization of Molecular Responses to Endurance Training (Methods) Using Genomic, Proteomics, Metabolomics and Protein Immunomics Techniques
Differential analysis was used to characterize the molecular responses to endurance training (Methods). The significance of the training response was calculated by taking 35,439 features that were at 5% false discovery rate and adding them together to get the training-regulated differential features. Timewise summary statistics quantify the exercise training effects for each sex and time point. Training-regulated molecules were observed in the vast majority of tissues for all omes, including a relatively large proportion of transcriptomics, proteomics, metabolomics and immunoassay features (Fig. 1c). The observed effects were not much more than the maximum folds change between 0.67 and 1.5. Permutation testing showed that permuting the group or sex labels resulted in a significant reduction in the number of selected analytes in most tissues (Extended Data Fig. 3a–d and Supplementary Discussion). For transcriptomics, the hypothalamus, cortex, testes and vena cava had the smallest proportion of training-regulated genes, whereas the blood, brown and white adipose tissues, adrenal gland and colon showed more extensive effects (Fig. 1c). The heart, lungs, and kidneys had more restricted results in both post-translational modifications and protein abundance compared to the gastrocnemius. A large proportion of differential metabolites were observed in all tissues, even if the absolute numbers were related to the number of metabolomic platforms used. The huge number of differential features over the course of the training time course shows the complex nature of adaptation to endurance training.
Whole blood, plasma and 18 solid tissues were analysed using genomics, proteomics, metabolomics and protein immunoassay technologies, with most assays performed in a subset of these tissues (Fig. 1b and Extended Data Fig. 1e,f There are details for each omics analysis in the table. The heart, lungs, kidneys and hippocampus were prioritized based on available tissue quantity and biological relevance, followed by the gastrocnemius, heart, adipose tissue, and white adipose tissue. Altogether, datasets were generated from 9,466 assays across 211 combinations of tissues and molecular platforms, resulting in 681,256 non-epigenetic and 14,334,496 epigenetic (reduced-representation bisulfite sequencing (RRBS) and assay for transposase-accessible chromatin using sequencing (ATAC-seq)) measurements, corresponding to 213,689 and 2,799,307 unique non-epigenetic and epigenetic features, respectively.
Molecular biologist Bente Pedersen: Managing the crosstalk between physical and physiological aspects of exercise in people with chronic diseases reveals that exercising is medicine too
When Bente Klarlund Pedersen wakes up in the morning, the first thing she does is pull on her trainers and go for a 5-kilometre run — and it’s not just about staying fit. According to the University of Copenhagen physician, it is when he does not know what he is doing that he can solve problems. It is very important for my well-being.
In 2020, Snyder and his colleagues took blood samples from 36 people aged between 40 and 75 years old before, during and at various time intervals after the volunteers ran on a treadmill. The team used profiling to measure more than 17,000 molecules and half showed significant changes after exercise. They found that exercising causes an elaborate study of certain biological processes such as energy metabolism. Creating a catalogue of exercise molecules is an important first step in understanding their effects on the body, says Snyder.
But researchers are just beginning to work out the meaning of this cacophony of crosstalk, says Atul Shahaji Deshmukh, a molecular biologist at the University of Copenhagen. A single molecule is not enough in the system, says Deshmukh, a mountain biker. “It’s an entire network that functions together.”
Researchers hope that the reams of molecular data will eventually help clinicians to develop tailored exercise prescriptions for people with chronic diseases, says MoTrPAC team member Bret Goodpaster, an exercise physiologist at the University of Pittsburgh in Pennsylvania. Farther down the track, such insights could be used to develop therapeutics that mimic some of the beneficial effects of exercise in people who are too ill to work out, he says. “That’s not to say that we will have exercise in a pill, but there are certain aspects of exercise that could be druggable,” says Goodpaster, who has taken part in triathlons, marathons and cycling races.
The work could also offer clues about which types of physical activity can benefit people with chronic illnesses, says Klarlund Pedersen. She says that she thinks you can prescribe exercise as soon as you can prescribe a medicine.
The human evolutionary stories are based on exercise. Although other primates evolved as fairly sedentary species, humans switched to a hunter-gatherer lifestyle that demanded walking long distances, carrying heavy loads of food and occasionally running from threats.
Researchers have been exploring some of the biological changes that occur during exercise for more than a century. In 1910, pharmacologist Fred Ransom at the University of Cambridge, UK, discovered that skeletal muscle cells secrete lactic acid, which is created when the body breaks down glucose and turns it into fuel5. And in 1961, researchers speculated that skeletal muscle releases a substance that helps to regulate glucose during exercise6.
It is possible for high levels of IL6 to be beneficial or harmful. At rest, too much IL-6 has an inflammatory effect and is linked to obesity and insulin resistance, a hallmark of type 2 diabetes, says Klarlund Pedersen. But when exercising, the molecule activates its more calming family members, such as IL-10 and IL-1ra, which tone down inflammation and its harmful effects. The anti-Inflammation response is caused by the intensity of each bout of exercise. Although some physical activity is better than none, high-intensity, long-duration exercise that engages large muscles like running or cycling is more likely to increase IL-6 production.
The act of exercising is a balancing act as well. Physical activity produces cellular stress, and certain molecules counterbalance this damaging effect. When mitochondria — the powerhouses that supply energy in cells — ramp up production during exercise, they also produce more by-products called reactive oxygen species (ROS), which, in excessive amounts, can damage proteins, lipids and DNA. But these ROS also kick-start a horde of protective processes during exercise, offsetting their more toxic effects and fortifying cellular defences.
Some studies look at how exercise affects cell types. A 2022 study in mice led by Jonathan Long, a pathologist at Stanford University, identified more than 200 types of protein that were expressed differently by 21 cell types in response to exercise10. The researchers were expecting to find that cells in the liver, muscle and bone would be most sensitive to exercise, but to their surprise, they found that a much more widespread type of cell, one that appears in many tissues and organs, showed the biggest changes in the proteins that it cranked out or turned down. The findings suggest that more cell types shift gears during a workout than was previously thought, although what these changes mean for the body is still an open question, says Long.
The distant organs and tissues communicate with each other during a workout. According to Mark Febbraio who is now an exercise physiologist, the mechanism behind organ and tissue crosstalk could be the same as exerkines: the creation of bubble-shaped structures called EVs. Febbraio and the team inserted tubes into 11 healthy men’s arteries and drew their blood after they rode an exercise bike for an hour. During and after exercise, but not at rest, they found a spike in the levels of more than 300 types of protein that compose or are carried by EVs11.
Most of the EV ended up in the cells of the body, as the team collected them after injecting them into mice that had run on a treadmill. In a separate mouse study that is yet to be published, Febbraio and his colleagues found hints that the contents of these liver-bound EVs can arrest a type of liver disease. A big question is whether EVs also deposit genetic material into different cells, and if so, what that means for the body. “We still don’t know a great deal,” he says.
Source: Why is exercise good for you? Scientists are finding answers in our cells
Why Does Exercise Have Diverse Effects on People of Different Ages, Ages and Ethnic Backgrounds? A Conversation with Rob Snyder at MoTrPAC
A big goal is to uncover why exercise has such varied effects on people of different sexes, ages and ethnic backgrounds, says Snyder, who is a member of the MoTrPAC team. “It’s very obvious that some people benefit better than others,” he says.