The body’s own protein cocktail makes muscles grow

Muscle stem cells The body’s own protein cocktail makes muscles grow

During growth, during sports, and after injuries – muscles have to grow from time to time. A research team in Berlin has now found that a mixture of three proteins produced in an oscillatory fashion plays a prominent role in this.

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When a muscle grows, for example because its owner has started exercising regularly, some of the stem cells in the muscle form new muscle cells. (Icon image)

(Image: Public Domain)

Berlin – When a muscle grows because its owner is still developing himself or has started exercising regularly, some of the stem cells in the muscle form new muscle cells. The same thing happens when a muscle is injured and begins to heal. However, at the same time, muscle stem cells also have to form additional stem cells, that is, they have to renew themselves, otherwise their supply will be consumed very quickly. This requires the cells involved in muscle growth to communicate with each other.

The path of the incision controls muscle growth

Two years ago, a team led by Professor Carmen Birchmeier, who heads the “Evolutionary Biology / Signal Transmission in Nerve and Muscle Cells” working group at the Max Delbrück Center for Molecular Medicine at the Helmholtz Society (MDC) in Berlin, showed that the stem cells can develop into muscle cells They are controlled with the help of two types of proteins, Hes1 and MyoD, which oscillate in primary cells – that is, they are produced cyclically, sometimes in larger and sometimes smaller amounts.

Both proteins participate in the Notch signaling pathway, a widely used mechanism by which cells interact with external stimuli and communicate with each other. The signaling pathway is named after its receptor “Notch”, on which the ligand anchors “Delta”, which is a surface protein of another cell.

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Delta-like1 – the third critical protein in the league

“In our current study, we have now presented clear evidence that oscillation in muscle tissue is not just a strange phenomenon in the cells in question, but that these rhythmic fluctuations in gene expression are really necessary for the transformation of controlled stem cells into muscle cells and they only occur in a limited range,” he added. Birchmeier says.

Stem cells on muscle fibers (gray).  Stem cells produce Dll1 (red) and MyoD (green).  Two of the cells produce MyoG (blue): they make new muscle cells.  Overlay of blue, green and red appears in white.
Stem cells on muscle fibers (gray). Stem cells produce Dll1 (red) and MyoD (green). Two of the cells produce MyoG (blue): they make new muscle cells. Overlay of blue, green and red appears in white.

(Photo: AG Birchmeier, MDC)

In collaboration with researchers from Japan and France, Birchmeier and four other scientists at the Center for Disease Control (MDC) have also decoded the crucial third protein role that, along with Hes1 and MyoD, forms a dynamic network in cells.

As the team reports in Nature Communications, Notch ligand Delta-like1 or Dll1 for short. “It is produced in activated muscle stem cells, oscillating periodically with an oscillation time of two to three hours”: Birchmeier explains: When one portion of the stem cells expresses more Dll1, the amount present in the other cells is less. “These rhythmic signals determine whether the stem cell forms a new stem cell or develops into a muscle cell.”

The Hes1 protein determines the frequency of stem cells

Birchmeier and her team also investigated the involvement of Hes1 and MyoD proteins in muscle growth in their experiments with isolated stem cells, individual muscle fibers, and mice. “In simple terms, it can be said that Hes1 acts as a pacemaker for oscillation, while MyoD increases Dll1 expression,” Dr. Ines Lahmann of the Birchmeier Working Group, who is the first author of the study along with Yao Zhang of the same team. “Our empirical analyzes not only showed both, but also the mathematical models that Professor Jana Woolf and Dr. Katarina Boom demonstrated in the MDC,” adds Birchmeier.

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Experiments with modified mice provided the definitive evidence

The most significant evidence that Dll1 oscillation is really crucial for the controlled transformation of stem cells into muscle cells has been presented by researchers with the help of transgenic mice. “A specific mutation in the Dll1 gene causes these animals to produce the protein within a few minutes,” explains Birchmeier. “This disrupts the oscillatory production of Dll1 in cell clusters, but does not alter the total amount of ligands.”

“However, the mutation has dangerous effects on stem cells, which turn prematurely into muscle cells and fibers,” says Zhang, who has conducted most of the experiments. Thus stem cells were used very quickly. One consequence of this was that the injured muscle in the hind legs of the mice did not regenerate sufficiently and remained smaller than it was before the injury. “Obviously, this minimal gene change is able to disrupt successful communication – in the form of a fluctuation – between stem cells,” says Zhang.

A study at the University of Bonn identified a molecule in mice that regulates two side effects of aging - increased body weight and muscle contraction.  Human cells also contain this molecule.  (Icon image)

Treat muscle diseases better

Birchmeier’s conclusion: “Only when Dll1 binds to the Notch receptor in an oscillatory fashion and thus periodically adjusts the signaling chain in stem cells in motion, is there clearly a good balance between self-renewal and cell differentiation.” The MDC researcher hopes that a better understanding of muscle regeneration and growth will one day help treat muscle injuries and diseases more effectively than before.

the origin Yao Zhang et al: Delta-like1 oscillations regulate the balance between differentiation and maintenance of muscle stem cells, In Nature Communications, DOI: 10.1038 / s41467-021-21631-4.

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* J. Ehrhardt-Joswig: Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin

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