Exploiting myoblast fusion process for muscle regeneration

Neuromuscular disorders affect millions of people worldwide. Now a discovery made opens the door to the development of targeted therapies.

The formation of muscles, a complex process, requires the action of specialized cells, the myoblasts. In order for skeletal muscle to develop and regenerate, myoblasts must align with each other, move towards each other, and touch each other until their membranes are joined. This is called the myoblast fusion stage and is the basis for the formation of muscle fibers.

During embryogenesis, myoblast fusion is crucial, with mutations in certain genes resulting in the 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.

“Until recently, myoblast fusion was the subject of only basic research," said the author.

"We weren't interested in it in the context of 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 contribute to the development of targeted therapies."

Myoblast fusion include RAC1 and its activator DOCK1. In the current study the authors analyzed the contribution of the DOCK1-interacting ELMO scaffold proteins to myoblast fusion. When Elmo1−/− mice underwent muscle-specific Elmo2 genetic ablation, they exhibited severe myoblast fusion defects.

A mutation in the Elmo2 gene that reduced signaling resulted in a decrease in myoblast fusion. Conversely, a mutation in Elmo2 coding for a protein with an open conformation increased myoblast fusion during development and in muscle regeneration. The authors also showed that the dystrophic features of the Dysferlin-null mice, a model of limbgirdle muscular dystrophy type 2B, were reversed when expressing ELMO2 in an open conformation.

"We also observed that this mouse model, when crossed with a mouse modeling limb-girdle muscular dystrophy 2B, can improve disease phenotypes," said the author.

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

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

The potential to manipulate the myoblast fusion step will undoubtedly be the subject of future studies, said the researchers.