Regulation of the growth of multinucleated muscle cells by an NFATC2-dependent pathway

The nuclear factor of activated T cells (NFAT) family of transcription fact ors regulates the development and differentiation of several tissue types. Here, we examine the role of NFATC2 in skeletal muscle by analyzing adult N FATC2(-/-) mice. These mice exhibit reduced muscle size due to a decrease i n myofiber cross-sectional area, suggesting that growth is blunted. Muscle growth was examined during regeneration after injury, wherein NFATC2-null m yofibers form normally but display impaired growth. The growth defect is in trinsic to muscle cells, since the lack of NFATC2 in primary muscle culture s results in reduced cell size and myonuclear number in myotubes. Retrovira l-mediated expression of NFATC2 in the mutant cells rescues this cellular p henotype. Myonuclear number is similarly decreased in NFATC2(-/-) mice. Tak en together, these results implicate a novel role for NFATC2 in skeletal mu scle growth. We demonstrate that during growth of multinucleated muscle cel ls, myoblasts initially fuse to form myotubes with a limited number of nucl ei and that subsequent nuclear addition and increases in myotube size are c ontrolled by a molecular pathway regulated by NFATC2.