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Body and mind

Protein’s kiss of death regulates muscles after exercise

Danish and Australian research shows how ubiquitin plays a key role in regulating protein degradation and adapting skeletal muscle following exercise. This process is important for maintaining a healthy body and healthy muscles, says a researcher.

After a good workout, the body has to build the muscles and their energy stores but also clear out the proteins that have passed their expiration date.

New Danish and Australian research shows that ubiquitin, also called the kiss-of-death protein, plays a very important role in removing potentially damaged proteins following exercise.

Ubiquitin attaches to the worn-out proteins, which is a signal to the cells’ debris collectors to degrade them and convert them into their key components in the form of amino acids that can be used to build new proteins for the muscles.

“We have shown that the activity of ubiquitin in the muscles increases dramatically after exercise, which indicates that a major clean-up is underway,” explains a researcher behind the new study, Erik A. Richter, Professor and Head of Section, Department of Nutrition, Exercise and Sports, University of Copenhagen.

The research, which was carried out in collaboration with the University of Sydney, has been published in The FASEB Journal.

Explains why physical activity is healthy

Physical activity is the basis of good health, and good health also includes developing and maintaining sound muscles that are essential for good mobility but also play a role in regulating metabolism.

This is why the muscles need to be healthy.

Part of the effort to keep the muscles healthy is to clean them up and remove the damaged proteins that have outlived their usefulness. They must be removed so that new and functioning proteins can replace them.

“Since this clean-up process is so important to ensure healthy muscles, knowing how it works is important. Long term, there may also be some pharmaceutical options that can influence the process of keeping the muscles and body healthy,” says Erik A. Richter.

Australians identified an active protein in muscle biopsies

The researchers got six healthy, untrained 26 to 28 year-old men to cycle intensely for 8–10 minutes and then took muscle biopsies from their thighs immediately after the exercise and 2 and 5 hours later.

The researchers also took biopsies from the participants at rest.

The Danish researchers sent the biopsies to colleagues in Australia, who are very skilled at mass spectrometry of muscles, a technique that can map the content of proteins in a biological sample.

Ubiquitin increases after exercise

The results showed that the activity of ubiquitin increased dramatically after intense exercise compared with the resting state.

Researchers already know ubiquitin and its function as conferring the kiss of death that condemns other proteins to destruction.

The study showed that ubiquitin sentenced far more proteins to death after exercise than at rest.

After ubiquitin places its kiss of death on the proteins, they are transported to be destroyed by the molecular structure called the proteasome, which degrades the proteins into amino acids.

The cells can then reuse the amino acids to make new proteins to keep the muscles functioning.

“Many types of proteins are broken down so that the muscle cells can build new ones. If the cells cannot break down the proteins properly, they accumulate and harm the cells in the long term,” explains Erik A. Richter.

Muscles activate their own clean-up mechanism

The research results are not surprising, because the researchers know about the function of ubiquitin and are aware of the need for cleaning up muscle cells at work.

However, researchers have not been entirely certain whether ubiquitin plays a significant role in cleaning up worn-out proteins during muscle activity.

The other two Danish researchers behind the study, Jørgen Wojtaszewski and Bente Kiens, indicate that the results substantiate why exercising is healthy.

“This explains part of the reason why physical activity is healthy, and then the great thing is that the muscles themselves activate the mechanisms that keep them updated, healthy and functional,” says Jørgen Wojtaszewski and Bente Kiens.

Finding the on-and-off switch for ubiquitin

The research also suggests how the body activates ubiquitin to clean up the muscles.

As the activity of ubiquitin increases and decreases in relation to physical activity, an on-and-off switch is required, which is the protein NEDD8 according to Erik A. Richter.

Like ubiquitin, NEDD8 is activated by exercise and appears to precede the activation of ubiquitin.

“NEDD8 is above ubiquitin, and the fact that this mechanism exists is new knowledge. Training activates NEDD8. The activation of NEDD8 involves cyclic AMP, which is formed when the muscles are affected by the high concentrations of adrenaline circulating in the blood during hard work,” says Erik A. Richter.

Erik A. Richter also says that more knowledge is needed on the role of ubiquitin in training.

The researchers still have to determine how different types of exercise affect the ubiquitin-activated clean-up process and whether this process is as important among women and older people as it is among young men.

Quantification of exercise‐regulated ubiquitin signaling in human skeletal muscle identifies protein modification cross talk via NEDDylation” has been published in The FASEB Journal. In 2017, the Novo Nordisk Foundation awarded a grant to Erik A. Richter for the project Defining the AMPK-mediated Signalling Network and its Function.

Erik A. Richter
Professor
My primary research interests are regulation of muscle metabolism, particularly during and following exercise. This includes acute exercise and exercise training. Emphasis has been on regulation of glucose metabolism and muscle glucose uptake during exercise as well as regulation of insulin sensitivity following exercise and training. Besides the deep interest in revealing physiological and molecular mechanisms, the objectives are to delineate the molecular mechanisms behind the positive health effects of exercise. We know very well that basically all forms of exercise have positive health effects but we have little knowledge about the molecular mechanisms that are responsible for these effects. These mechanisms are important to understand as they might reveal novel drug candidate pathways that could be beneficial for prevention and treatment of metabolic and cardiovascular diseases.