Gαi2 Signaling Promotes Skeletal Muscle Hypertrophy, Myoblast Differentiation, and Muscle Regeneration

Skeletal muscle atrophy results in loss of strength and an increased risk of mortality. We found that lysophosphatidic acid, which activates a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, stimulated skeletal muscle hypertrophy through activation of G alpha(i2). Expression of a constitutively active mutant of G alpha(i2) stimulated myotube growth and differentiation, effects that required the transcription factor NFAT (nuclear factor of activated T cells) and protein kinase C. In addition, expression of the constitutively active G alpha(i2) mutant inhibited atrophy caused by the cachectic cytokine TNF alpha (tumor necrosis factor-alpha) by blocking an increase in the abundance of the mRNA encoding the E3 ubiquitin ligase MuRF1 (muscle ring finger 1). G alpha(i2) activation also enhanced muscle regeneration and caused a switch to oxidative fibers. Our study thus identifies a pathway that promotes skeletal muscle hypertrophy and differentiation and demonstrates that G alpha(i2)-induced signaling can act as a counterbalance to MuRF1-mediated atrophy, indicating that receptors that act through G alpha(i2) might represent potential targets for preventing skeletal muscle wasting.