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The key to correct muscle growth



The key to correct muscle growth

Immunofluorescence analysis of a group of proliferating stem cells related to muscle fibers (grey). Stem cells produce Dll1 (red) and MyoD (green). Two of the cells produce MyoG (blue): they are differentiating to form new muscle cells. Note that the overlay of blue, green, and red is displayed in white.Image source: MDC Birchmeier Laboratory

When the muscle grows, some stem cells in the muscle will develop into new muscle cells because the owner is still growing or has begun regular exercise. The same thing happens when the injured muscle starts to heal. However, at the same time, muscle stem cells must produce more stem cells (ie, self-renew), otherwise their supply will quickly run out. This requires the cells involved in muscle growth to communicate with each other.

Muscle growth is regulated by Notch signaling pathway

Two years ago, a team led by Professor Carmen Birchmeier, Head of the Developmental Biology/Signal Transduction Laboratory at the Max Delbrück Center for Molecular Medicine in Berlin at the Helmholtz Society (MDC) Group researchers showed that the developmental muscle cells of stem cells are regulated by two proteins, Hes1 and MyoD, which are produced in an oscillating manner in progenitor cells, that is, the number of cells produced periodically fluctuates.

Both proteins are involved in the Notch signaling pathway, which is a broad mechanism for cells to respond to external stimuli and communicate with other cells. The signaling pathway is named after its receptor “Notch”, and the ligand “Delta” (cell surface protein) is locked on it.

The third protein, Delta-like1, plays a vital role

“In our current research, we have provided clear evidence that the oscillation of muscle tissue is not only a strange phenomenon in the cells involved, but also that the rhythmic fluctuations in the expression of these genes are actually critical to the condition of balance and control. The next step is to transform stem cells into muscle cells. The way,” Birchmeier said.

Birchmeier and four other scientists at MDC, together with researchers from Japan and France, also discovered the key role of a third protein, which, together with Hes1 and MyoD, forms a dynamic network within the cell.As the team reported in the diary Nature Communications, The protein is Notch ligand Delta-like1, or Dll1 for short. “It is produced in the activated muscle stem cells in a cyclical manner. The oscillation period lasts for two to three hours,” Birchmeier explained, adding: “Whenever some stem cells express more Dll1, other cells The number will increase. This rhythmic signal determines whether the stem cell becomes a new stem cell or develops into a muscle cell.”

Hes1 protein determines the pace of stem cells

In experiments on isolated stem cells, individual muscle fibers and mice, Birchmeier and her team further investigated how Hes1 and MyoD proteins are involved in muscle growth. “Simply put, Hes1 acts as a pacemaker, and MyoD increases the expression of Dll1,” said Dr. Ines Lahmann, a scientist in Birchmeier’s laboratory, the lead author of the study, and Yao Zhang from the same group. Birchmeier said: “These findings are not only proven in our experimental analysis, but also in the mathematical model created by Professor Jana Wolf and Dr. Katharina Baum of MDC.”

Experiments with mutant mice provide decisive evidence

With the help of genetically modified mice, the researchers obtained the most important evidence that Dll1 oscillation plays a crucial role in regulating the transformation of stem cells into muscle cells. Birchmeier explained: “In these animals, specific mutations in the Dll1 gene cause protein production to occur and delay for a few minutes.” “This disrupts the oscillatory production of Dll1 in the cell population, but does not change the total amount of ligand.”

“Nevertheless, this mutation has serious consequences for stem cells, prompting them to differentiate into muscle cells and fibers prematurely,” said Zhang, who conducted most of the experiments. He said that as a result, the stem cells were quickly depleted, which in particular led to poor regeneration of the injured muscles in the hind legs of the mice, which were smaller than the muscles before the injury. Zhang said: “It is clear that this minimal genetic change managed to disrupt the successful communication between stem cells, in the form of oscillations.”

This knowledge may lead to better treatments for muscle diseases

“Only when Dll1 binds to Notch receptors in an oscillating manner and thus periodically initiates the signal transduction cascade in stem cells, can the cell’s self-renewal and differentiation reach a good balance,” Birchmeier concluded. MDC researchers hope that one day a better understanding of muscle regeneration and growth may help create more effective treatments for muscle injuries and diseases.


Oscillations in muscle tissue


More information:
Yao Zhang et al. The oscillation of Delta-like1 regulates the balance between differentiation and maintenance of muscle stem cells, Nature Communications (2021). DOI: 10.1038 / s41467-021-21631-4

Courtesy of Max Delbrück Center for Molecular Medicine



Citation: The key to proper muscle growth (February 26, 2021) is retrieved from https://medicalxpress.com/news/2021-02-key-proper-muscle-growth.html to February 27, 2021

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