Epigenetics: How sport changes our cells

Spektrum der Wissenschaft

5.6.2020

Translation: machine translated

Sport can change our genetic make-up - more precisely, the molecular markers that control genes. Experts want to use this to determine which sport benefits whom the most.

Numerous studies prove this: People who exercise reduce their risk of diabetes, cardiovascular disease and certain types of cancer. Because our bodies are designed for life as hunters and gatherers, we need plenty of exercise - otherwise we get sick. Conversely, this means: If you do a lot of sport, will you stay healthy in any case? Not necessarily. Because not everyone benefits from exercise in the same way. Why is that the case? And: what actually changes in our cells when we regularly pedal, lift weights or go for a run?

Many research groups are now focussing on the second question in particular. Although there are not yet any large studies that reveal the specific connections, there are exciting observations: A team led by biologist Birgitte Regenberg from the University of Copenhagen, for example, scrutinised the muscle cells of 16 healthy men between the ages of 60 and 65. Half of the test subjects had done a lot of sport throughout their lives. The study revealed that the genetic material of the athletic men differed from that of the non-athletic men in more than 700 places.

The researchers did not look at the sequence of letters in the genetic code, but at small chemical changes that had subsequently taken place. Experts refer to these as epigenetic changes. For example, the DNA bases adenine and cytosine can carry a methyl group. These appendages influence the accessibility of the DNA. Genes that are decorated with a particularly large number of methyl groups in certain regions, for example, are generally more difficult to read.

Genes that are needed for energy production, muscle building or protection against free radicals were less methylated in the athletic older men than in the non-athletic test subjects. As a result, these genes are more frequently transcribed and translated into the corresponding proteins, as Regenberg's team discovered.

Not only the DNA - its packaging is also important

Whether brain, muscle or liver cells - in principle, each of our cells contains the same genetic material. Epigenetics, among other things, determines which genes are read and give the cell its typical appearance and function. You can think of it as a kind of text formatting: The cell uses certain markers to recognise which parts of the genome are particularly important.

Not only the DNA itself, but also the proteins bound to it can be epigenetically modified. Our genetic material is by no means lying around naked in the cell nucleus, but is wrapped around barrel-shaped protein complexes, the histones, like a thread on a spool. These also carry methyl or acetyl groups at certain points - or not. If the histones are tipped with acetyl groups, this loosens up the compact wrapped structure and the genes can be read more easily (see infographic "A meta-level of regulation").

Even small snippets of genetic material - called micro-RNA - can change the extent to which genes are utilised. When a gene is read, the cell first produces a copy in the form of RNA, which in turn serves as a template for proteins, for example. Micro-RNAs can bind to these intermediates. This can lead to the corresponding protein no longer being produced - the gene is effectively silenced. Some micro-RNAs, on the other hand, stabilise or activate a specific gene. Experts assume that around 50 per cent of the genes that provide the building instructions for a particular protein are regulated by micro-RNAs.

Many of these epigenetic changes already take place during embryonic development - they are largely fixed. In other places, the epigenetic signature can change over the course of life. Scientists from all over the world are trying to find out what these changes are and what effect they have in detail. "The field of research is still relatively young, but the increase in knowledge is enormous," says Barbara Munz from the University Hospital of Tübingen.

With her working group, the biochemist is investigating how muscle cells react to physical training. Most studies to date - including those by Regenberg and her colleagues - are more descriptive, says Munz. They are looking at where epigenetic changes occur in the genetic material of people who exercise. Because many of the studies are very expensive and time-consuming, they usually only involve a handful of test subjects. In addition, it is often difficult to find enough volunteers who fulfil the necessary requirements and stay on the ball throughout the study period, explains Munz.

What a certain histone change or DNA methylation actually does is difficult to find out, says the biochemist. This has to be investigated in cell culture experiments or using animal models. Research teams have already done this for some genes or signalling pathways. But a mouse or a rat runs very differently from a human. And how do you get a cell culture to do sport? Electrical pulses can be used to cause muscle cells to contract. However, this in no way reflects the complex processes that physical training triggers in our muscles, says Munz.

Why exercise helps against diabetes

One of the most important effects of regular exercise is that you build up muscle mass. This not only makes us look better, but also boosts our metabolism. We react more sensitively to insulin, the hormone that controls the absorption of sugar into our cells. This mechanism is disrupted in people with diabetes.

"The great thing is that you can also regulate your blood sugar levels with exercise," says pharmacologist Annette Schürmann. That's why she always advises diabetics to increase their physical activity. At the German Institute of Human Nutrition in Potsdam-Rehbrücke, Schürmann is investigating which genetic and epigenetic changes lead to the development of diabetes. From this, the researchers hope to gain new insights into the treatment of this widespread disease.

Exercise causes our muscle cells to absorb more glucose - regardless of insulin levels. This is because they incorporate more of a certain transporter protein into their membrane. A team led by Edward Ojuka from the University of Cape Town wanted to find out which epigenetic changes this is linked to. The researchers gave rats swimming training and looked at a section of DNA that is particularly important for the production of the transporter. Something had actually changed here in the trained rats: Their histones carried more acetyl groups. This is why the gene for the glucose transporter was read more frequently in them.

In order to treat diabetes or prevent the metabolic disease, you also have to change your diet in the long term, says Schürmann. Being overweight is one of the main risk factors for type 2 diabetes. Sport can help you lose weight. However, it has now been shown that exercise has much less influence on our body weight than previously thought. What and how much you eat is apparently much more important. In addition, diet also causes epigenetic changes. The good news is that these can be reversed - at least in part. Even those who have been eating a poor diet for years, for example eating a lot of fat and carbohydrates, can still do something to stop diabetes with a change in diet and exercise.

How much sport is necessary?

On the other hand, it is now also known that not only genetic traits, but also epigenetic traits can be passed on - to the next generation and probably even the generation after that. "Sport and nutrition also change something in our germ cells," says Schürmann. These are the cells that we produce in our reproductive organs, i.e. sperm and eggs. Experiments with mice have shown, for example, that the offspring of animals that have eaten a high-fat diet are more prone to obesity and diabetes. For many experts, there is no question that epigenetic changes are the cause.

To find out whether this is similar in humans, a team led by diabetes researcher Charlotte Ling from the Swedish University of Lund analysed the epigenome of 28 men with an average age of 37.5 years. All of the men were healthy but unathletic. 15 participants were directly related to someone who suffered from type 2 diabetes. In some of them, the team found different methylation patterns in genes involved in energy and insulin metabolism. However, after a six-month training programme, some of these patterns had changed.

This is also an indication that it is still worth starting to exercise in middle or old age. Munz agrees: "Positive effects are recognisable at any age," says the biochemist. It is particularly important for older people to counteract muscle loss. Not only endurance sports, but also light strength training can make a big difference here. If possible, you should combine strength and endurance training - and consult your doctor.

How much sport is necessary to observe epigenetic changes? Does even a single session have an effect? "In principle, yes," says Wilhelm Bloch from the German Sport University in Cologne. Every sporting activity is a stimulus and means high pressure to adapt, says the sports physician. Some studies indicate that even a single training session triggers epigenetic changes. According to Schürmann, however, these differ significantly from the traces that regular sport leaves behind. She assumes that these changes can only be observed after three months of training at the earliest. How long they persist is still largely unclear.

"Over the course of our lives, the methylation pattern of many genes changes," says Bloch. As we get older, more methyl groups accumulate in many areas. Some genes that prevent the development of cancer are therefore less active - one reason why our cancer risk increases with age. Sport can counteract this, says Bloch. Genes involved in the inflammatory response, on the other hand, are often less methylated in older people. They are therefore transcribed more frequently and have a pro-inflammatory effect. To find out whether this can also be influenced by exercise, a team led by Shun'ichiro Taniguchi from Shinshu University in Japan had around 200 older people complete a regular workout for six months. Afterwards, the researchers actually found more methylation in an important inflammatory gene. Regular exercise can apparently counteract age-related inflammatory processes.

Genetics and epigenetics influence each other

So why do some people still fall ill even though they have done sport all their lives? This question is not easy to answer. Firstly, it can be stated that it is not only epigenetic characteristics, but also small, subtle deviations in our genetic code that influence which genes are read and how well the proteins we produce function. The genetic background plays a particularly important role in diabetes, says Schürmann. "We know that more than 400 sites in the sequence of our genetic material are linked to the development of diabetes."

Scientists used to think that such sequence differences were the only way to explain why people are particularly susceptible to certain diseases. The fact that this explanation is not sufficient can be seen, for example, in identical twins. Although their genetic make-up is identical, they do not necessarily develop the same diseases.

In fact, epigenetics and genetics influence each other, says Bloch. For example, if someone has a particularly high number of cytosines in a certain gene, it can be methylated particularly strongly. This can ultimately have both positive and negative effects on the person's performance and health. It is difficult to estimate what influence sport - and the associated change in methylation - would have.

In addition to exercise and diet, there are many other factors that can alter our epigenome. "Alcohol, for example, is an excellent epigenetic regulator," says Bloch. He therefore tells his students that going to the pub is like an epigenetic experiment. In cell culture experiments, he has observed that even the smallest amounts of alcohol lead to methyl groups being attached to and removed from the DNA more easily. "When investigating epigenetic changes as a result of sport, you should therefore always ask: what else do people do?" the sports medicine specialist notes. The whole package is very complex.

"At the moment, we are still a long way from being able to predict which epigenetic change causes what," says Munz. However, she believes that in future it will be possible to use a person's epigenetic profile to predict whether they will respond to a particular training programme. As part of the project "Individual Response to Physical Activity - A Transdisciplinary Approach (iReAct)", Munz and her colleagues are currently conducting a study on young, healthy people. They are completing two different forms of endurance training for six weeks each. The research team observes the increase in performance of the people and analyses their muscle tissue for certain epigenetic characteristics, in this case micro-RNAs. The initial results have already revealed a pattern, says Munz. "Perhaps we will be able to make a recommendation to people in the future - even if we don't yet understand the mechanisms behind it."

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