During skeletal muscle growth and regeneration, the majority of differentiating myoblasts undergoes cell-cell fusion to form multinucleated myofibers, whereas a proportion of myoblasts undergoes apoptosis. The treatment of myoblasts with prostaglandin F2alpha (PGF2alpha) during myogenesis in vitro leads to the formation of large myotubes, but the mechanism by which PGF2alpha promotes myotube growth has not been investigated. Here, we demonstrate that PGF2alpha reduces cell death during myogenesis in vitro and in vivo. In addition, we show that PGF2alpha increases expression of the inhibitor of apoptosis protein (IAP) BRUCE through a pathway dependent on the nuclear factor of activated T cell 2 transcription factor. Importantly, PGF2alpha-mediated reduction in muscle cell death is dependent on BRUCE, and overexpression of BRUCE is sufficient to promote muscle cell survival and growth. These results establish a previously unrecognized link between NFAT signaling and regulation of IAP expression and are the first to identify a signaling pathway that increases BRUCE expression. In addition, our results provide evidence that increasing the pool of muscle cells available for fusion by inhibiting cell death enhances myotube growth.