All vertebrates need muscles to function; they are the most abundant tissue in the human body and are integral to movement.
In a recent article published in Nature Communications, an international team of researchers discovered two proteins essential to the development of skeletal muscle. This research, could lead to a better understanding of rare muscular diseases and the development of new treatments.
Skeletal muscles are attached to our bones and enable our bodies to move. Whether in a developing embryo or a professional athlete, the same sequence leads to their formation.
"In vertebrates, cells derived from stem cells, called myoblasts, first align with each other and come so close as to eventually touch and compress their cell membranes," explained the study's lead author.
Ultimately, myoblasts merge to create one large cell. This phenomenon, called "cell fusion", is very particular. "Cell fusion involves just a few tissues, including the development of the placenta and the remodeling of our bones," the author said. BAI3 is a receptor that orchestrates myoblast fusion via Elmo/Dock1 signaling, but the mechanisms regulating its activity remain elusive.
To develop and also repair muscle, myoblasts have to perform their movements very carefully. No false move is permissible, otherwise there will be defects. Authors show that mice lacking BAI3 display small muscle fibers and inefficient muscle regeneration after cardiotoxin-induced injury. They describe two proteins that repress or activate BAI3 in muscle progenitors. Authors find that the secreted C1q-like1–4 proteins repress fusion by specifically interacting with BAI3.
Using a proteomic approach, authors identify Stabilin-2 as a protein that interacts with BAI3 and stimulates its fusion promoting activity. They demonstrate that Stabilin-2 activates the GPCR activity of BAI3. The resulting activated heterotrimeric G-proteins contribute to the initial recruitment of Elmo proteins to the membrane, which are then stabilized on BAI3 through a direct interaction.
Indeed, ClqL4 and Stabilin-2 ensure successful completion of this delicate sequence. They slow down and trigger cell fusion respectively at key moments. Their role is crucial: if the "metronome" of myoblasts is interrupted, the muscles will not be the right size, and their function will be affected. This is what happens in muscle diseases characterized by a weakness that makes certain movements difficult.
The researchers have already embarked on the follow-up study. They want to determine whether the results of their research could become a therapeutic target for rare muscle diseases such as myopathies and muscular dystrophies.
https://www.nature.com/articles/s41467-018-06897-5
