Gαi2 Signaling Is Required for Skeletal Muscle Growth, Regeneration, and Satellite Cell Proliferation and Differentiation

We have previously shown that activation of G alpha i2, an alpha subunit of the heterotrimeric G protein complex, induces skeletal muscle hypertrophy and myoblast differentiation. To determine whether G alpha i2 is required for skeletal muscle growth or regeneration, G alpha i2-null mice were analyzed. G alpha i2 knockout mice display decreased lean body mass, reduced muscle size, and impaired skeletal muscle regeneration after cardiotoxin-induced injury. Short hairpin RNA (shRNA)-mediated knockdown of G alpha i2 in satellite cells (SCs) leads to defective satellite cell proliferation, fusion, and differentiation ex vivo. The impaired differentiation is consistent with the observation that the myogenic regulatory factors MyoD and Myf5 are downregulated upon knockdown of G alpha i2. Interestingly, the expression of microRNA 1 (miR-1), miR-27b, and miR-206, three microRNAs that have been shown to regulate SC proliferation and differentiation, is increased by a constitutively active mutant of G alpha i2 [G alpha i2(Q205L)] and counter-regulated by G alpha i2 knockdown. As for the mechanism, this study demonstrates that G alpha i2(Q205L) regulates satellite cell differentiation into myotubes in a protein kinase C (PKC)- and histone deacetylase (HDAC)-dependent manner.