A combinatorial role for NFAT5 in both myoblast migration and differentiation during skeletal muscle myogenesis.

Skeletal muscle regeneration depends on myoblast migration, differentiation and myofiber formation. Isoforms of the nuclear factor of activated T cells (NFAT) family of transcription factors display nonredundant roles in skeletal muscle. NFAT5, a new isoform of NFAT, displays many differences from NFATc1-c4. Here, we examine the role of NFAT5 in myogenesis. NFAT5+/- mice displayed a defect in muscle regeneration with fewer myofibers formed at early times after injury. NFAT5 has a muscle-intrinsic function because inhibition of NFAT5 transcriptional activity caused both a migratory and differentiation defect in cultured myoblasts. We identified Cyr61 as a target of NFAT5 signaling in skeletal muscle cells. Addition of Cyr61 to cells expressing inhibitory forms of NFAT5 rescued the migratory phenotype. These results demonstrate a role for NFAT5 in skeletal muscle cell migration and differentiation. Furthermore, as cell-cell interactions are crucial for myoblast differentiation, these data suggest that myoblast migration and differentiation are coupled and that NFAT5 is a key regulator.