Ferlin proteins in myoblast fusion and muscle growth

Abstract

Myoblast fusion contributes to muscle growth in development and during regeneration of mature muscle. Myoblasts fuse to each other as well as to multinucleate myotubes to enlarge the myofiber. The molecular mechanisms of myoblast fusion are incompletely understood. Adhesion, apposition, and membrane fusion are accompanied by cytoskeletal rearrangements. The ferlin family of proteins is implicated in human muscle disease and has been implicated in fusion events in muscle, including myoblast fusion, vesicle trafficking and membrane repair. Dysferlin was the first mammalian ferlin identified and it is now known that there are six different ferlins. Loss-of-function mutations in the dysferlin gene lead to limb girdle muscular dystrophy and the milder disorder Miyoshi Myopathy. Dysferlin is a membrane-associated protein that has been implicated in resealing disruptions in the muscle plasma membrane. Newer data supports a broader role for dysferlin in intracellular vesicular movement, a process also important for resealing. Myoferlin is highly expressed in myoblasts that undergoing fusion, and the absence of myoferlin leads to impaired myoblast fusion. Myoferlin also regulates intracellular trafficking events, including endocytic recycling, a process where internalized vesicles are returned to the plasma membrane. The trafficking role of ferlin proteins is reviewed herein with a specific focus as to how this machinery alters myogenesis and muscle growth.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1

Schematic of the mammalian ferlin family members. The ferlins share similar domain architecture: a carboxy-terminal transmembrane domain and multiple amino-terminal C2 domains, including a C2A domain that has been shown to bind negatively charged phospholipids in dysferlin and myoferlin. The DYSF domain is the putative binding site of caveolin-3 and is found within dysferlin, myoferlin, and fer1L5.

Figure 2

A Phylogram of the mammalian ferlin family. Dysferlin and myoferlin are closely related. Fer1L5 also shares close relation to dysferlin and myoferlin, while fer1L4, otoferlin, and fer1L6 are distantly related. B Throughout myoblast differentiation, myoferlin (dark grey) is highly expressed in proliferating myoblasts and nascent myotubes, while dysferlin (light grey) is highly expressed in mature myotubes.

Figure 3

Membrane fusion events in muscle repair. Shown is a site of muscle injury. At the top is myoblast to myofiber fusion. The middle portion reflects myoblast to myoblast fusion. The lower portion of the picture depicts plasma membrane disruption undergoing resealing. Ferlin family members, particularly, dysferlin and myoferlin, are poised to mediate these events.

Figure 4

Model of ferlin-mediated endocytic recycling that contributes to myoblast-myoblast fusion, myoblast-myotube fusion, and membrane damage repair. Ferlin-interacting actinbinding proteins (ferlins – string of beads; AHNAK – boomerang shape) remodel the actin cytoskeleton, allowing endocytosis of ligand-bound receptors. Ferlins mediate fusion of endocytosed vesicles with the endocytic recycling compartment (ERC) where the ligand is removed. EHD proteins (wishbone shape) participate in the scission of recycling vesicles from the ERC. EHD proteins interact with the ferlins for transport back to the plasma membrane. EHD proteins also interact with EHBP1 (trapezoid) for actin cytoskeletal rearrangement, and ferlin proteins assist in fusion of recycling vesicles to the sarcolemma.