Researchers used stressed cells to discover new muscle protein

Diet and lifestyle 9. okt 2022 3 min Professor Simon Bekker-Jensen Written by Kristian Sjøgren

Researchers have discovered a protein that is essential in building muscles. Injecting the protein into muscles causes the muscles to grow 50% without requiring exercise. The discovery may have implications for people with myopathy and frail older people.

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An international group of researchers wanted to determine how cells react to stress. They ended up finding a new protein that seems to play a fundamental role in building muscles.

The discovery of the ZAK-beta protein is interesting because it suggests potentially being able to activate muscle building without requiring exercise.

This might sound like doping, but this discovery could strongly affect a completely different group of people.

“Loss of muscle mass is a huge problem for hospitalised older people. Bedridden people lose muscle mass. Younger people recover muscle quickly, but older people do not, and this is a major health problem. If artificially activating this protein can stimulate muscle building while older people are bedridden, this would be great,” explains a researcher behind the discovery, Simon Bekker-Jensen, Professor, Department of Cellular and Molecular Medicine, University of Copenhagen.

The research has been published in EMBO Journal.

Cells embedded in agarose and compressed

The discovery began with the researchers’ desire to determine what happens to cells’ signalling when compressed. This stresses them, but researchers do not yet understand how cells respond to this stress.

Cells can be compressed in different ways. Lung cells, skin cells and cells in the heart and bones are compressed all the time, and this causes them to send various signals so that they can constantly adapt to this stress.

The researchers fixed cells in agarose and then compressed the agarose while observing how the cellular signalling pathways responded.

“We know about the stress enzymes that are activated when the cells are stressed, but we had not been able to identify the gene that translates pressure on the cells into activation of these signals downstream. This is a missing piece of the puzzle for understanding this whole cellular response. Our research involved determining how the compression of a cell is detected by which mechanisms and how they do it,” says Simon Bekker-Jensen.

Protein does not function among people with muscle disorders

The research resulted in the discovery of a protein capable of identifying compression in the cells.

The protein, called ZAK-beta, binds to an internal cellular structure, a scaffolding that ensures that the cells do not collapse on their own.

When a cell is compressed, this internal scaffolding is deformed, and ZAK-beta detects this.

“This was a basic scientific discovery, but we wanted to know more and found out that the gene for ZAK-beta has also previously been linked to myopathy, a specific muscle disorder characterised by muscle weakness,” explains Simon Bekker-Jensen.

Missing gene produced flabby muscles

In the next part of the research, the researchers collaborated with muscle physiologists who can stimulate muscle growth in the muscles of mice by inserting an electrode into the lower legs and then electrically stimulating the muscles to work.

Then the researchers could examine the muscles and determine whether the electrical stimulation activated the signalling pathways needed to stimulate muscle building after muscle work.

The researchers performed this with both normal mice and mice that had had the gene for ZAK-beta knocked out, and the signalling pathways needed to build muscle were never activated.

Among people, this results in myopathy.

“This enabled us to understand the molecular process that causes people with ZAK-beta mutations to be unable to build muscle. If ZAK-beta does not function, you cannot activate the muscle-building signalling pathways, and then you do not have healthy muscles. Now we know why this gene and protein are important for muscles and muscle disorders,” says Simon Bekker-Jensen.

Induced muscles to grow by 50%

However, the researchers continued their investigations, injecting the gene itself into muscles from mice. Then the muscle cells begin to express the gene and thereby produce a lot of ZAK-beta.

The muscle fibres grew by 50%. For humans, this would correspond to injecting the gene for ZAK-beta into an upper arm and causing it to grow by 50%.

“This is interesting because our research thus shows not only that ZAK-beta is necessary for healthy muscle growth but also that overexpressing ZAK-beta can increase the size of the muscle fibres. These two facts mean that we have found the missing signalling pathway that connects muscle work to muscle growth,” explains Simon Bekker-Jensen.

Could people skip exercise?

Simon Bekker-Jensen thinks that the discovery contains several perspectives.

A drug that stimulates the activation of ZAK-beta inside the muscle cells can potentially build good, healthy muscles without people spending any time in a gym.

“This will primarily be relevant for people who are not physically able to train sufficiently or whose muscles do not have the normal capacity to respond positively to resistance training, such as hospitalised or bedridden older people,” says Simon Bekker-Jensen.

Could be dangerous

Before we reach the stage in which a pill might replace 90 minutes of strenuous training in the gym, however, ZAK-beta needs to be studied further.

The researchers need to investigate whether injecting the gene into the muscles of mice solely results in larger muscles or whether there are side-effects.

There may be specific reasons why ZAK-beta is carefully regulated in the body and not expressed in huge quantities.

Overexpressing the protein might not just lead to bigger muscles but perhaps also to dysfunctional muscles. Activating too much of this protein in the heart could also be dangerous.

“This is the next step in the research. We need to determine what activating ZAK-beta really means for the whole body and whether any side effects will be associated with it,” concludes Simon Bekker-Jensen.

The overarching aim for our group is to understand the molecular details of cellular stress responses and how they contribute to human diseases such a...

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