A research laboratory lead by Jean-François Côté at the Institut de Recherches Cliniques de Montréal, Montreal, Canada has identified an elusive protein that mediates the fusion of muscle precursor cells into mature muscle.
The development of skeletal muscles depends on the migration of muscle precursor cells called “myoblasts” to migrate to the right location and then fuse with each other to form the multi-nucleate skeletal muscle cells. This finding has the potential to improve the treatment of muscular diseases such as myopathies and muscular dystrophies.
“For several years, we have been studying myogenesis, a process by which muscles are formed during development,” said Côté.
In the fruit fly Drosophila melanogaster, muscle fusion is rather well understood. A protein called “Myoblast City” and a scaffolding protein called “ELMO” activate the Rac protein in response the muscle precursor cells adhering to surfaces. Rac initiates the intracellular mechanisms that culminate in muscle fusion. In vertebrates, the ELMO protein exists in muscle precursor cells and a vertebrate version of the myoblast city protein called DOCK1. However, identifying the receptor that kicks this process off had proven difficult.
Myoblast fusion plays a central role in muscle development because it determines muscle size. Also, the fusion of existing muscle fibers with muscle stem cells helps regenerate and maintain adult muscles. This fusion process has always been a poorly understood process.
However, Côté and his co-workers have identified a receptor called BAI3 as one of the crucial links in myoblast fusion. BAI3 activates a signaling process that initiates the fusion of nearby myoblasts.
In 2008, Côté and his colleagues elucidated the role of two proteins – DOCK1 and DOCK5 – in the development of muscles. DOCK1 and DOCK5 regulate myoblast fusion. When the interaction between BAI3 and the DOCK signaling proteins is inhibited, myoblast fusion is also inhibited.
Côté pointed out that this work could have far-reaching implications, since the delivery of functional proteins to diseased muscle is typically carried out by introducing genetically engineered stem cells into the muscle that fuse with the disease muscle. By increasing the efficiency of the muscle fusion process, the delivery of genes to diseased muscles could become routine rather than painstakingly inefficient.