The key to good muscle growth

When a muscle grows, because its owner is still growing or has started exercising regularly, some of that muscle’s stem cells turn into new muscle cells. The same thing happens when an injured muscle begins to heal. At the same time, however, the muscle stem cells have to produce other stem cells, i.e. renew themselves, as their supply would otherwise be depleted very quickly. This requires that the cells involved in muscle growth communicate with each other.

Muscle growth is regulated by the Notch signaling pathway

Two years ago, a team of researchers led by Professor Carmen Birchmeier, head of the developmental biology / signal transduction laboratory at the Max Delbrück Center for Molecular Medicine of the Helmholtz Association (MDC), showed that the development of stem cells in muscle cells are regulated with the help of two proteins, Hes1 and MyoD, which are produced in progenitor cells in an oscillatory manner, that is, there are periodic fluctuations in the number of cells produced.

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

A third protein, Delta-like1, plays a crucial role

“In our current study, we have provided unequivocal evidence that oscillation in muscle tissue is not only a strange phenomenon of the cells involved, but that these rhythmic fluctuations in gene expression are in fact crucial for transforming stem cells into muscle cells in a balanced and controlled manner. Says Birchmeier.

In collaboration with Japanese and French researchers, Birchmeier and four other scientists at MDC also discovered the crucial role of a third protein which, together with Hes1 and MyoD, forms a dynamic network within cells. As the team reports in the newspaper Nature communications, this protein is the Notch Delta-like1 ligand, or Dll1 for short. “It is produced in the activated muscle stem cells in a periodically fluctuating fashion, the period of oscillation lasting two to three hours,” explains Birchmeier, adding: “Whenever part of the stem cells express more Dll1, the amount in other cells This rhythmic signaling determines whether a stem cell becomes a new stem cell or develops into a muscle cell. “

Hes1 protein sets the tone in stem cells

In their experiments with isolated stem cells, individual muscle fibers, and mice, Birchmeier and his team further investigated how the Hes1 and MyoD proteins are involved in muscle growth. “Simply put, Hes1 acts as the oscillatory stimulator, while MyoD increases Dll1 expression,” says Dr. Ines Lahmann, Birchmeier lab scientist and lead author of the study with Yao Zhang from the same team. “These results were demonstrated not only in our experimental analyzes, but also in the mathematical models created by Professor Jana Wolf and Dr Katharina Baum at MDC,” says Birchmeier.

Experiments with mutant mice have provided decisive evidence

With the help of genetically engineered mice, researchers obtained the most important evidence that the Dll1 oscillation plays a critical role in regulating the transformation of stem cells into muscle cells. “In these animals, a specific mutation in the Dll1 gene causes production of the protein with a delay of a few minutes,” explains Birchmeier. “This disrupts the oscillatory production of Dll1 in cell communities, but does not alter the overall amount of the ligand.”

“Nevertheless, the mutation has serious consequences on the stem cells, causing them to differentiate prematurely into muscle cells and fibers,” reports Zhang, who performed much of the experiments. As a result, he says, the stem cells were depleted very quickly, which resulted in, among other things, an injured muscle in the mouse’s hind legs regenerating poorly and remaining smaller than before the injury. “Obviously, this minimal genetic change manages to disrupt the successful communication – in the form of oscillation – between stem cells,” says Zhang.

This knowledge could lead to better treatments for muscle disease

“It is only when Dll1 binds to the Notch receptor in an oscillatory fashion and thus periodically initiates the signaling cascade in stem cells that there is a good balance between self-renewal and differentiation in cells”, concludes Birchmeier. The MDC researcher hopes that a better understanding of muscle regeneration and growth could one day help create more effective treatments for muscle injuries and diseases.