Inositol 1,4,5 trisphosphate receptor 1 is a key player of human myoblast differentiation.

Cytosolic Ca(2+) signals are fundamental for the early and late steps of myoblast differentiation and are, as in many cells, generated by Ca(2+) release from internal stores as well as by plasma membrane Ca(2+) entry. Our recent studies identified the store-operated Ca(2+) channels, Orai1 and TRPC1&C4, as crucial for the early steps of human myogenesis and for the late fusion events. In the present work, we assessed the role of the inositol-1,4,5 tris-phosphate receptor (IP3R) type 1 during human myoblast differentiation. We demonstrated, using siRNA strategy that IP3R1 is required for the expression of muscle-specific transcription factors such as myogenin and MEF2 (myocyte enhancer factor 2), and for the formation of myotubes. The knockdown of IP3R1 strongly reduced endogenous spontaneous Ca(2+) transients, and attenuated store-operated Ca(2+) entry. As well, two Ca(2+)-dependent key enzymes of muscle differentiation, NFAT and CamKII are down-regulated upon siIP3R1 treatment. On the contrary, the overexpression of IP3R1 accelerated myoblasts differentiation. These findings identify Ca(2+) release mediated by IP3R1 as an essential mechanism during the early steps of myoblast differentiation.