10 August 2022

Researchers crack the code to muscle generation


Loss of muscle mass presents a challenge especially among hospitalized elderly. It complicates treatment, rehabilitation and may result in reduced quality of life after bring discharged. However, researchers from the University of Copenhagen have recently identified a protein that the body uses to generate muscle mass and have even succeeded in artificially triggering it.

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"The long and exciting perspective is finding a way to activate the ZAK-beta-protein through medication and artificially maintain or grow muscle mass in patients, without them having to be mobile,” says Professor Simon Bekker-Jensen

Being immobile for just a few days significantly reduces your muscle mass. This is especially problematic in health practice, where immobility is often an extension of being hospitalized. Furthermore, the road towards rebuilding lost muscle mass becomes steeper with age – potentially so steep that the patient may never recover the strength from before they were admitted.

However, that dilemma may soon become less problematic, as an international team of researchers spearheaded by the Center for Healthy Aging have identified the specific signaling mechanism that informs the muscles that they are being used. This finding may enable artificially maintaining or increasing muscle mass – even in people that are unable to move.

The findings have just been published in EMBO Journal. The study has mapped the bodily process of muscle contraction and identified the concrete signal that induces muscle generation.

“The puzzle piece that we have found is the ZAK-beta-protein, which becomes activated upon contraction. This means that we have found the protein that informs the muscle that it is working, and the sensor that informs the body that this work needs to be translated into new muscle generation,” says Professor Simon Bekker-Jensen from the Center for Healthy Aging, who led the team of researchers.

Muscle loss haunts the hospitals

Muscle loss among patients is often an unfortunate extension of being hospitalized. The immobility, that often comes with being admitted to the hospital, can complicate the patients’ recovery in the long run.

“Muscle loss among hospitalized patients is a significant problem in practice, as it can affect the patient long after they have been discharged,” says Charlotte Suetta, Professor at the University of Copenhagen, Center Director at CopenAge and Chief Physician at Bispebjerg-Frederiksberg and Gentofte-Herlev Hospital.

“Loss of muscle mass causes reduced physical function, and that has profound effect on the individual’s quality of life.”

According to Charlotte Suetta, muscle loss through immobility is surprisingly swift. The muscle fiber area is reduced by 10% in just four days of immobility among healthy individuals. The loss is even greater if the patient is acutely ill and in need of interventions such as mechanical ventilation, as was the case during the Covid-pandemic.

Additionally, the patients’ age has significant impact on how fast the recovery time is.

“Muscle loss affects both young and elderly, but the younger patients have an easier time recovering their muscle mass, while it is a bigger workload for the elderly patients after being discharged. This also means that there is a much greater risk that the elderly patients cannot recover the physical function they had before being hospitalized,” says Charlotte Suetta.

Mutation recreated in mice

The discovery of the ZAK-beta-protein has come through an extremely rare case of muscle weakness (myopathy), with just six known cases of the mutation worldwide. These patients all lack the gene that produce the ZAK-beta-protein in the muscle.

“The nerve signals to the brain when a muscle is used have been mapped out before. But the muscle itself also needs to know how much and how intensely it is being used, as this has profound impact on the processes that change the composition of the muscle. That is the new mechanism we have found with the ZAK-beta-protein,” says Ph.D. student Cathrine Nordgaard, first author on the study.

To verify the ZAK-beta-protein’s significance for muscle generation, the researchers recreated the myopathy-mutation in mice.

They then sedated the mice and sent electric impulses into the specific nerves of a hindleg that made the muscle exert what amounts to 10 minutes of intense training. The researchers then recorded biometric data for muscle generation.

“We could see that the muscle from both normal and mutated mice had used up all its stored sugar – its energy. But in the mice without the ZAK-beta-protein, the biomarker for muscle generation was not activated. We could activate the muscle just like normal, but the muscle did not properly register that it was being used. The work did not translate into the process that we know is needed to generate muscle mass,” says Cathrine Nordgaard.

A ’bodybuilder protein’

This insight into the process of muscle generation has significant health perspectives. Not least due to its potential use to counteract muscle loss in the future, which may benefit immobile patients.

According to Simon Bekker-Jensen, the researchers have experimented with overexpressing the ZAK-beta-protein in specific muscle fibers in mice. This resulted in a 50% increase in the cross-sectional area of the fibers even though the mice were not being exercised.

“We did this by injecting droplets of the gene that codes for the ZAK-beta-protein into the muscle and then applying an electrical field for gene delivery. This would be far too invasive for a patient. So, the long and exciting perspective is finding a way to activate the ZAK-beta-protein through medication and artificially maintain or grow muscle mass in patients, without them having to be mobile,” he says.

The next step for the team of researchers is therefore to explore the effects on mice, if they live their whole life with the ZAK-beta-protein on overdrive. While the work so far has been funded by Lundbeckfonden, the next steps for the project is funded by Novo Nordisk Fonden.

“If we can overexpress this signaling protein, and it turns out to be purely beneficial for muscle size and growth, the following step will be to start developing medicine that can artificially kickstart this mechanism of muscle development. I am quite confident that this is technically possible, but it might take quite some years to get there,” says Simon Bekker-Jensen.

Read the article “ZAKb is activated by cellular compression and mediates contraction-induced MAP kinase signaling in skeletal muscle” here.


Professor Simon Holst Bekker-Jensen
+45 35 32 50 24

Communication and Outreach Consultant Thomas Sten Pedersen
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