Anoctamin 5/TMEM16E facilitates muscle precursor cell fusion.

Limb-girdle muscular dystrophy type 2L (LGMD2L) is a myopathy arising from mutations in ; however, information about the contribution of ANO5 to muscle physiology is lacking. To explain the role of ANO5 in LGMD2L, we previously hypothesized that ANO5-mediated phospholipid scrambling facilitates cell-cell fusion of mononucleated muscle progenitor cells (MPCs), which is required for muscle repair. Here, we show that heterologous overexpression of ANO5 confers Ca-dependent phospholipid scrambling to HEK-293 cells and that scrambling is associated with the simultaneous development of a nonselective ionic current. MPCs isolated from adult mice exhibit defective cell fusion in culture and produce muscle fibers with significantly fewer nuclei compared with controls. This defective fusion is associated with a decrease of Ca-dependent phosphatidylserine exposure on the surface of MPCs and a decrease in the amplitude of Ca-dependent outwardly rectifying ionic currents. Viral introduction of in MPCs restores MPC fusion competence, ANO5-dependent phospholipid scrambling, and Ca-dependent outwardly rectifying ionic currents. -rescued MPCs produce myotubes having numbers of nuclei similar to wild-type controls. These data suggest that ANO5-mediated phospholipid scrambling or ionic currents play an important role in muscle repair.