Mechanisms of myoblast fusion during muscle development

Abstract

The development and regeneration of skeletal muscle require the fusion of mononucleated muscle cells to form multinucleated, contractile muscle fibers. Studies using a simple genetic model, Drosophila melanogaster, have discovered many evolutionarily conserved fusion-promoting factors in vivo. Recent work in zebrafish and mouse also identified several vertebrate-specific factors required for myoblast fusion. Here, we integrate progress in multiple in vivo systems and highlight conceptual advance in understanding how muscle cell membranes are brought together for fusion. We focus on the molecular machinery at the fusogenic synapse and present a three-step model to describe the molecular and cellular events leading to fusion pore formation.

Figure 1. The three-step model describing the cellular events leading to fusion pore formation in myoblast fusion

Step 1 – The initial cell adhesion between a founder cell and an FCM is mediated by Ig domain-containing CAMs. Step 2 – Following cell adhesion, the FCM generates actin-propelled membrane protrusions to invade the apposing founder cell, the latter of which mounts a myosin II-mediated mechanosensory response to increase the cortical tension and therefore cortical resistance to the FCM invasion. Step 3 – once the two plasma membranes are brought into close proximity by the invasive and resistance forces, the lipid bilayers are destabilized, leading to the formation of a fusion pore. A hypothetical scenario depicted here is that PS could be flipped from the inner to the outer leaflet, resulting in a more disorganized outer leaflet prone to fusion.

Figure 2. Signaling pathways leading to asymmetric F-actin and myosin accumulation in Drosophila myoblast fusion

Trans-interaction between cell type-specific CAMs, such as Duf (founder cell; with 5 Ig domains) and Sns (FCM; with 8 Ig domains), triggers distinct signaling events in founder cells and FCMs. Briefly, in the founder cell, activation of Scar results in the formation of a thin sheath of F-actin at the fusogenic synapse. In addition, the Rho1-Rok-MyoII pathway amplifies the mechanosensitive accumulation of MyoII at the fusogenic synapse. In the FCM, activation of both Scar and WASP leads to the formation of an F-actin-enriched focus, which is part of an invasive podosome-like structure. For the functions of other components shown here, see the text.

Figure 3. Signaling components required for vertebrate myoblast fusion in vivo

Due to the lack of molecular and cellular markers for the fusogenic synapse in vertebrates, the localization and potential sidedness of these proteins are hypothetical.