Researchers make groundbreaking discovery in muscle regeneration

[Apr. 2, 2023: Julie Gazaille, University of Montreal]

Stem cells, responsible for the formation of skeletal muscles, could make it possible to repair muscles damaged by diseases. (CREDIT: Creative Commons)

The fusion of myoblasts, stem cells responsible for the formation of skeletal muscles, could make it possible to repair muscles damaged by diseases such as muscular dystrophy.

Neuromuscular diseases affect millions of people worldwide. Now, a discovery made at the Montreal Clinical Research Institute (IRCM) opens the door to the development of targeted therapies.

Published in the journal Nature Communicationthe development crowns several years of research by doctoral student Viviane Tran under the direction of professor of medicine at the University of Montreal Dr. Jean-François Côté, president and scientific director of the IRCM, with international partners.

The formation of muscles, a complex process, requires the action of specialized cells, the myoblasts. For skeletal muscle to grow and regenerate, myoblasts must align with each other, move toward each other, and touch each other until their membranes come together. This is called the myoblast fusion stage and is the basis of muscle fiber formation.

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During embryogenesis, myoblast fusion is crucial, with mutations in certain genes resulting in an extremely rare clinical myopathy called Carey-Fineman-Ziter syndrome.

In adults, an army of satellite cells is responsible for muscle growth and regeneration. In response to activation signals, satellite cells proliferate, differentiate and fuse to repair damaged myofibers. The proteins and signaling pathways that control this fusion are still being identified.

“We didn’t think it was possible”

“Until recently, myoblast fusion was only the subject of basic research,” said Dr. Côté.

Manipulation of ELMO2 conformational regulation regulates myoblast fusion in a cell-intrinsic manner. a fusion test carried out with primary myoblasts isolated from the indicated mice after 72 h of differentiation. (CREDIT: Nature Communications)

“We were not interested in it in the context of the disease; we didn’t think it was possible to use this process to cure certain diseases. Yet understanding in detail all the factors involved in this fusion could help in the development of targeted treatments. therapies. »

In a key experiment, the researchers created a mouse model in which a protein involved in the fusion is expressed in its active mammalian form. During muscle development and regeneration, an increase in myoblast fusion has been observed.

Isothermal titration calorimetry determined a binding affinity of 10.3 μM for RHOG and WT ELMO2, whereas no binding could be measured for the L43A mutant. (CREDIT: Nature Communications)

“We also observed that this mouse model, when crossed with a mouse modeling girdle muscular dystrophy 2B, can improve disease phenotypes,” Tran said.

Direct evidence of usefulness

The new data therefore provide direct evidence that the process of myoblast fusion could be exploited for regenerative purposes and to improve the outcome of muscle diseases.

Manipulation of conformational regulation of ELMO2 impacts myoblast fusion during muscle development and growth. (CREDIT: Nature Communications)

In the long term, this research shows that increasing cell fusion could “repair” muscles in other types of muscular dystrophy, such as Duchenne dystrophy (occurring in 1 in 4,000 boys) or other serious conditions , such as cachexia (secondary muscle breakdown due to various diseases and some forms of cancer).

The potential for manipulating the myoblast fusion step will no doubt be the subject of future studies, said the researchers, who worked with colleagues at UdeM’s Institute for Research in Immunology and Cancer) and the IRCM, in Montreal and internationally.

For more scientific news, see our New discoveries section on The bright side of the news.

Note: The documents provided above by Montreal university. Content may be edited for style and length.

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