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Oscillation Of Proteins Halts Stem Cell Differentiation In Muscles.

Researchers Find That Stable Protein Production Is Crucial

BERLIN, Germany, March 15, 2019 -- When a muscle becomes injured, new muscle cells must develop as quickly as possible.

Likewise, when a muscle must grow, because of normal growth or increased physical activity, the conversion of stem cells is also required.

"At the same time, however, there needs to be a mechanism in the body that prevents an uncontrolled differentiation of stem cells, because otherwise the supply of these cells in the muscles would be quickly depleted," said Carmen Birchmeier, of the Max Delbruck Center for Molecular Medicine in the Helmholtz Association 'MDC).

Birchmeier and a multinational group of colleagues conducted mouse experiments that examined how this mechanism works.

They report that the MyoD and Hes1 proteins that regulate the differentiation of muscle cells are produced in the stem cells in an oscillatory manner--i.e., there are periodic fluctuations in the number of cells produced.

"This observation, first of all, was astonishing in itself," said Birchmeier, "because no one before us had detected the oscillation of proteins in muscle."

Such a phenomenon was previously only observed in stem cells of the brain.

The researcher hopes her studies will one day lead to better treatments of muscular dystrophies and of sarcopenia, a syndrome characterized by the progressive loss of muscle mass with advancing age.

"We started off by connecting the Hesl and MyoD to proteins to light-emitting proteins so that we could better track their development," said Ines Lahmann, the study's lead author.

The team was then able to observe--in isolated cells, in muscle tissue, and in living animals--that the Hesl protein, which is part of the Notch signaling pathway, is produced in an oscillatory manner.

"Production reaches its peak every two to three hours and then declines again," Lahmann said, adding that they encountered the same phenomenon in the MyoD protein. "As long as the quantity of MyoD in the stem cells fluctuates periodically, the cells grow and divide, thus renewing themselves," said Lahmann.

This ensures there is always a sufficient supply of stem cells in the muscle.

When a muscle stem cell starts to differentiate and develop into a muscle cell, one result is the formation of long muscle fibers. This occurs, for example, when a muscle grows in a young organism or when it tries to repair itself after an injury.

"Every time we observed this conversion of cells under the microscope, we had previously noticed that the oscillation had stopped and MyoD was expressed stably, regardless of whether we were looking at newborn or adult animals," said Birchmeier.

Her team then proceeded to turn the gene for Hes1 completely off, so that the protein is no longer produced in the stem cells.

The researchers conducted this experiment on both cells and living animals.

'The lack of Hes1 led to MyoD no longer being produced in an oscillatory manner, but rather in a stable pattern. All stem cells began to differentiate as a result," said Birchmeier.

"Our experiments show that when it comes to stem cell differentiation and probably many other cellular processes, genes are not simply turned on or off. But we are still a long way from understanding all the developments that occur when we use genetic tricks to do exactly that," Birchmeier said.

They next want to study why the oscillation of MyoD leads to stem cell differentiation not taking place in the muscles, and why a stable production of the protein is needed to trigger this process.

"Once we gain a better understanding of the whole process, we will be able to better help people with muscular disorders whose natural capacity for muscle regeneration has been impaired."

Citation: Ines Lahmann et al., Oscillations of MyoD and Hes1 proteins regulate the maintenance of activated muscle stem cells. Genes & Development, 2019; DOI: 10.1101/gad.322818.118


Contact: Carmen Birchmeier,
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Title Annotation:Basic Research
Publication:Stem Cell Research News
Date:Mar 25, 2019
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