Intracellular TMEM16A is necessary for myogenesis of skeletal muscle

Transmembrane protein 16A (TMEM16A) localizes at plasma membrane and con-trols chloride influx in various type of cells. We here showed an intracellular local-ization pattern of TMEM16A molecules. In myoblasts, TMEM16A was primarily localized to the cytosolic compartment and partially co-localized with intracel-lular organelles. The global deletion of TMEM16A led to severe skeletal muscle developmental defect. In vitro observation showed that the proliferation of Tmem16a-/- myoblasts was significantly promoted along with activated ERK1/2 and Cyclin D expression; the myogenic differentiation was impaired accompanied by the enhanced caspase 12/3 activation, implying enhanced endo-plasmic reticulum (ER) stress. Interestingly, the bradykinin-induced Ca2+ release from ER calcium store was significantly enhanced after TMEM16A deletion. This suggested a suppressing role of intracellular TMEM16A in ER calcium release whereby regulating the flux of chloride ion across the ER membrane. Our findings reveal a unique location pattern of TMEM16A in undifferentiated myoblasts and its role in myogenesis.