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Researchers develop a database linking exercise and genes

A new database provides researchers a rapid overview of whether exercise changes their favourite gene. The database can be used to rapidly answer many questions how exercise training or inactivity affects the body.

Researchers from the University of Copenhagen have developed a database that links exercise training to the expression of many genes.

Researchers can use the database to much more easily study how exercise training affects the exact gene that interests them.

This means that they can immediately determine whether exercise training affects a gene. They can also quickly shelve their trial plans if the database indicates that examining whether exercise training affects the gene makes no sense.

“Many studies have investigated small groups of people who have been asked to carry out some form of exercise training. The researchers then measured the expression of various genes in a muscle biopsy from the participants. However, getting meaningful results can be difficult because the studies are small scale. In this new database, we have integrated many studies to provide researchers with access to many more substantial data,” explains the researcher behind MetaMEx, Juleen R. Zierath, Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen and Professor of Physiology, Karolinska Institutet, Stockholm, Sweden.

The research behind MetaMEx has been published in Nature Communications.

MetaMEx compiles small studies into a catalogue of thousands of trial participants

Juleen R. Zierath and colleagues collected data from 66 published data sets from scientific studies to construct MetaMEx.

Each data set contained data from 10–50 participants, whom the researchers behind the studies had asked to perform different types of exercise training before measuring the expression of various genes through muscle biopsies.

For example, the researchers may have asked the participants to perform acute or chronic aerobic (endurance) training or resistance (weight) training or to remain inactive.

These individual small studies thereby linked various types of exercise training to the expression of various genes, as measured by the activity of messenger RNA, which translates the genetic code into the activity of proteins.

The expression of one gene and its associated protein may increase with aerobic training, and the expression of another gene decreases. This can also differ for different types of exercise training.

“But the problem is that small studies with only 10 to 50 people do not lead to very definitive conclusions. We therefore collect data from all of them in MetaMEx, so we link training with how genes are expressed among thousands of people,” explains Juleen R. Zierath.

Determining the sex-specific benefits of exercise training

Juleen R. Zierath presents examples of how MetaMEx can make research on the link between exercise training and gene expression much easier.

For example, a researcher is interested in gene X and would like to know whether acute resistance training upregulates it?

Instead of conducting a large and expensive study, the researcher can explore the many published data in MetaMEx to see how the gene reacts in a large study population.

Researchers can also investigate how exercise training affects the activity of genes in specific subgroups.

These may be subgroups of people with metabolic diseases such as insulin resistance, in which some genes may respond differently to exercise training among people with insulin resistance compared with people without insulin resistance.

Researchers can also investigate whether exercise training affects the expression of genes differently between the sexes.

“Very few studies have investigated how exercise specifically affects the activity of genes among women. Researchers who want to determine whether a specific type of physical activity affects the activity of a specific gene among men but not among women can use MetaMEx,” says Juleen R. Zierath.

Gene reacts most strongly to exercise training

Juleen R. Zierath and her colleagues have used MetaMEx to identify the NR4R3 gene as one of the genes most responsive to exercise and inactivity.

The expression of NR4R3 increases considerably with exercise training and decreases with inactivity.

By studying the actual function of NR4R3 in cell cultures, the researchers determined that this gene is important for mitochondrial biogenesis in cells – how well they convert fuel into energy.

The fact that NR4R3 has such an essential function makes sense since exercise training upregulates it and inactivity downregulates it.

“MetaMEx provides rapid access to this type of research. We identified a gene that is important for exercise training, and then we could study its function to better understand its role,” explains Juleen R. Zierath.

Researcher tweets about using MetaMEx

Researchers have already used the database, and co-author Javi Botella from Victoria University in Melbourne has even tweeted about MetaMEx, explaining how it has helped his research.

In January 2020, two studies published in Nature Communications (here and here) indicated that the sestrins play a role in exercise-related health benefits in mice and flies. The sestrins have also been linked to inactivity and age-related muscle weakness in mice.

Javi Botella was very interested in these two studies and wanted to investigate whether the genes also play the same role in humans.

Normally, as in the first study, he would have had to conduct a very expensive and time-consuming trial with participants who would have to train or be inactive for a given period of time before he could determine whether exercise training or inactivity up- or downregulates the expression of the sestrins.

However, this was not necessary, because he could instead search in MetaMEx and quickly see what other researchers had found among thousands of subjects.

MetaMEx revealed that exercise training does not strongly affect the sestrins in humans.

“Many researchers are examining interesting new biology in animals and cells and would like to know whether data exist for humans. Javi Botella would have spent a lot of time and money on a research dead end if he did not have access to those data. He can now use that money and time on other research projects, because MetaMEx quickly told him whether this was worth investigating further,” says Juleen R. Zierath.

Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity” has been published in Nature Communications. In 2017, the Novo Nordisk Foundation awarded an Advanced Grant to Juleen Zierath, Scientific Director, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen for the project Integrative Biology of Exercise.

Juleen Zierath
Scientific Director, Professor
Juleen Zierath's research focuses on cellular mechanisms underlying the development of insulin resistance in Type 2 Diabetes (T2DM). The overarching goal of her group is to identify and validate molecular targets that prevent or treat skeletal muscle insulin resistance in T2DM. Her group is taking a translational approach to resolve the mechanism for peripheral insulin resistance using cell-based systems, genetically modified animal models, and clinical material from T2DM patients. In particular, Juleen Zierath's group is investigating if synchronizing exercise and nutrient interventions to the molecular circadian clock can maximize the health promoting benefit of these interventions, to enhance insulin sensitivity and prevent T2DM. Juleen Zierath's has experimentally de-convoluted the complex interaction between distinct insulin signaling pathways that modulate divergent downstream metabolic and gene regulatory responses in skeletal muscle. She has published more than 210 research papers and 70 review articles, with key discoveries published in Science, Cell, Nature Genetics, and Cell Metabolism.