A New Role for Ion Channels in Myoblast Fusion

During myogenesis, proliferating myoblasts withdraw from the cell cycle and fuse to form an ordered array of large, multinucleated muscle fibers. This highly regulated process can be divided temporally into a series of complex steps: commitment to a myoblast phenotype, acquisition of fusion competence, recognition and adhesion of like myoblasts, fusion of myoblasts into multinucleated myo-tubes, and differentiation of myotubes into muscle fibers. The end result is differentiated muscle fibers that contain several characteristic proteins, including: specific types of actin, myosin, tropomyosin, and troponin (which form part of the contractile apparatus), creatine phosphokinase, nic-otinic receptors to respond to acetylcholine released from motor nerves, and various types of voltage-gated ion channels to generate actions potentials. Commitment to a myoblast phenotype is an event that occurs early during embryonic development (Cossu et al., 1996). The steps that occur down stream of this commitment , however, are still being worked out. Like many developmental processes, myogenesis is complex and difficult to investigate in normal vertebrate embryos. Fortunately, crucial steps in myogenesis can be recapitulated in tissue culture. This discovery, made several years ago, has greatly facilitated research in this area. Using myoblast fusion as a relatively easy readout of differentiation, many researchers have investigated molecular mechanisms involved in aspects of myogenesis. A central focus of this research has been to identify molecules that promote myoblast fusion and to determine changes in these cells as they differentiate. Several essential molecules involved in fusion have been identified, including cell adhesion molecules, calcium and calmodulin, metalloproteases, phospholipases, and lipids (Yagami-Hiro-masa et al., 1995; Tachibana and Hemler, 1999). As an alternative to tissue culture, some groups are working with Drosophila, thus enabling them to identify molecules crucial to myogenesis using a genetic approach. Myogenesis in Drosophila is similar to that in vertebrates (Doberstein et al., 1997; Frasch, 1999), and so it is likely that molecules that are important for myoblast differentiation and fusion in Drosophila will have homologues in vertebrates. A number of Drosophila genes that appear to be involved in myogenesis include: rolling stone (rost), myo-blast city (mbc), blown fuse (blow), dumbfounded (duf), and stick-and-stones (sns) (Frasch and Leptin, 2000). Recently, research has shown that the gene products of duf and sns are novel members of the immunoglobulin superfamily differentially expressed on developing myoblasts (Bour et al., 2000; Ruiz-Gomez et al., 2000). Both molecules act during the early stages of myoblast fusion and null mutations in …