Some people say a man is made out of mud
A poor man’s made out of muscle and blood
– Merle Travis, Sixteen Tons
Muscle fibers are unique, massive cells that contain many nuclei. They begin, like all animal cells, as naive embryonic cells. These cells then differentiate, producing intermediate cells called myoblasts, which, while not yet muscle, are already stamped with their future destiny. New myoblasts seek out other myoblasts, and when they find each other, they stick together like best friends. In the final stage of muscle fiber development, the cell membranes of the attached myoblasts open up and fuse together, forming one large, unified cell. The new muscle fiber is now complete, capable of contracting, stretching and working.
How myoblasts identify other myoblasts and how they cling together had been established, but the way that cell membranes fuse into one remained a mystery. A recent study by Weizmann Institute scientists has now shed light on this mystery. The study was carried out by research student Rada Massarwa and lab technician Shari Carmon under the guidance of Dr. Eyal Schejter and Prof. Ben-Zion Shilo of the Institute’s Molecular Genetics Department, with help from Dr. Vera Shinder of the Electronic Microscopy Unit.
The cells’ system for identifying other myoblasts and sticking to them consists of protein molecules that poke through the outer cell membrane – one end pointing out and the other extending into the body of the cell. Both ID scanner and anchor, these protein molecules are capable of recognizing each other and holding the cells in position next to each other. But the research team wondered what happens in the next stage, when the myoblasts open their doors to each other and merge into one cell.
The scientists discovered that a protein called WIP, which attaches to the internal part of the myoblast recognition protein, plays a key role in muscle cell fusion. WIP communicates between the identification molecule and the cell’s internal skeleton, which is made of tough, elastic fibers composed of a protein called actin. The skeletal actin applies force to the abutting cell membranes, tearing them open and enlarging those holes so that the cells can merge. The Weizmann Institute team found that the WIP protein is turned on by an external signal telling it that another myoblast has been identified and is now snuggled up close. Only when it receives this signal does WIP hook up the actin fibers in the skeleton to the myoblast recognition protein, enabling cell fusion to proceed.
The WIP protein has been conserved evolutionarily. In other words, versions of it exist in all animals, from microorganisms such as yeast, through worms and flies, and up to humans. Not only does this mean that the protein fulfills an important function necessary for life but also, say the scientists, because of this conservation, studies conducted on this protein in fruit flies can teach us quite a bit about how it works in humans.
To further examine the role of WIP, the scientists used sophisticated genetic research techniques to knock out the gene responsible for producing it in fruit flies. In flies that did not make the protein, normal muscle fibers failed to take shape. WIP-deficient myoblasts continued to identify and cozy up to one another, but fusion between cell membranes didn’t take place, and multi-nucleated muscle fibers failed to form. A scientific paper describing these findings appeared in the journal Developmental Cell.
This study, which improves our understanding of the process of muscle formation, may in the future assist in devising new and advanced methods for healing muscle. These might include, in particular, ways of fusing stem cells with injured or degenerated muscle fibers.
Fusion between cell membranes also plays a key role in the development of different kinds of bone cells, placental cells and immune system cells, as well as in fertilization and in the penetration of viruses into living cells. Understanding how membrane fusion takes place may one day lead to the development of ways to encourage the process when it’s needed or hinder it when it’s likely to cause harm.
Prof. Ben-Zion Shilo’s research is supported by the M. D. Moross Institute for Cancer Research; the Y. Leon Benoziyo Institute for Molecular Medicine; the Clore Center for Biological Physics; the Dr. Josef Cohn Minerva Center for Biomembrane Research; the J & R Center for Scientific Research; and the Jeanne and Joseph Nissim Foundation for Life Sciences Research. Prof. Shilo is the incumbent of the Hilda and Cecil Lewis Professorial Chair in Molecular Genetics.
Fruit fly muscle fibers:
The normal fibers consist of large multinucleated cells, while the mutant mucles are thin and disorganized, due to failure of muscle cells to fuse with the founder muscle cells.