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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 Gαi2. Expression of a constitutively active mutant of Gαi2 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 Gαi2 mutant inhibited atrophy caused by the cachectic cytokine TNFα (tumor necrosis factor–α) by blocking an increase in the abundance of the mRNA encoding the E3 ubiquitin ligase MuRF1 (muscle ring finger 1). Gαi2 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 Gαi2-induced signaling can act as a counterbalance to MuRF1-mediated atrophy, indicating that receptors that act through Gαi2 might represent potential targets for preventing skeletal muscle wasting.