Prostaglandin F_2α stimulates growth of skeletal muscle cells via an NFATC2-dependent pathway

Skeletal muscle growth requires multiple steps to form large multinucleated muscle cells. Molecules that stimulate muscle growth may be therapeutic for muscle loss associated with aging, injury, or disease. However, few factors are known to increase muscle cell size. We demonstrate that prostaglandin F_2α (PGF_2α) as well as two analogues augment muscle cell size in vitro. This increased myotube size is not due to PGF_2α-enhancing cell fusion that initially forms myotubes, but rather to PGF_2α recruiting the fusion of cells with preexisting multinucleated cells. This growth is mediated through the PGF_2α receptor (FP receptor). As the FP receptor can increase levels of intracellular calcium, the involvement of the calcium-regulated transcription factor nuclear factor of activated T cells (NFAT) in mediating PGF_2α-enhanced cell growth was examined. We show that NFAT is activated by PGF_2α, and the isoform NFATC2 is required for PGF_2α-induced muscle cell growth and nuclear accretion, demonstrating the first intersection between prostaglandin receptor activation and NFAT signaling. Given this novel role for PGF_2α in skeletal muscle cell growth, these studies raise caution that extended use of drugs that inhibit PG production, such as nonsteroidal antiinflammatory drugs, may be deleterious for muscle growth.