Muscle Fusion Protein Identified – Better Muscular Disease Treatment

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.

Drosophila myoblast fusion

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.

Myoblast fusion

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.

Using Bone Marrow Stem Cells to Reprogram Neurons and Regenerate the Retina

Spanish researchers from the Center for Genomic Regulation (CGR) have regenerated the retina in mice by reprogramming neurons with bone marrow stem cells.

Cell reprogramming normally uses genetic engineering techniques that introduces genes into cells that push them into another cell fate without taking them through an embryonic-like state. One strategy for reprogramming cells fuses those cells with other cells that express genes that drive the fused cell into a different cell fate.

Pia Cosma and her team have used cell fusion to reprogram retinal neurons in mice. The mechanism consisted of introducing bone marrow stem cells into the damaged retina. The transplanted stem cells fused with existing retinal neurons, which conveyed to these retinal neurons the ability to regenerate the retina.

“For the first time we have managed to regenerate the retina and reprogram its neurons through in vivo cell fusion. We have identified a signaling pathway that, once activated, allows the neurons to be reprogrammed through their fusion with bone marrow cells,” said Pia Cosma, who is the head of the Reprogramming and Regeneration group at the CGR and ICREA (Institució Catalana de Recerca i Estudis Avançats) research professor.

Daniela Sanges, first author or the work and postdoctoral researcher in Pia Cosma’s laboratory, said, “This discovery is important not only because of the possible medical applications for retinal regeneration but also for the possible regeneration of other nervous tissues.”

The study demonstrates that the regeneration of nervous tissue by means of cell fusion is possible in mammals and describes this new technique as a potential mechanism for the regeneration of more complex nervous tissue.

This research is in the very early stages but already there are laboratories interested in being able to continue the work and take it to a more applied level.

Daniela Sanges, Neus Romo, Giacoma Simonte, Umberto Di Vicino, Ariadna Diaz Tahoces, Eduardo Fernández, Maria Pia Cosma. Wnt/β-Catenin Signaling Triggers Neuron Reprogramming and Regeneration in the Mouse Retina . Cell Reports – 25 July 2013 (Vol. 4, Issue 2, pp. 271-286)