GH regulation of IGF-I and suppressor of cytokine signaling gene expression in C2C12 skeletal muscle cells

GH is required for normal postnatal growth and metabolism. GH stimulates po stnatal growth through induction of IGF-I gene expression. Although the liv er is the major site of GH-regulated IGF-I, recent evidence indicates that GH-regulated IGF-I expression in nonhepatic tissues is sufficient for norma l postnatal growth. One potentially important nonhepatic site of GH-stimula ted IGF-I expression is skeletal muscle, as injection of GH into animals le ads to increased IGF-I mRNA in this tissue. Nevertheless, direct effects of GH in skeletal muscle cells in culture have not been reported. We therefor e tested the C2C12 myogenic cell line for its response to GH and demonstrat e that C2C12 skeletal muscle cells rapidly respond to physiological levels of GH with increased tyrosine phosphorylation of the GH receptor, Janus kin ase 2, signal transducer and activator of transcription-5a and -5b, insulin receptor substrate-1, and activation of MAPKs/ERKs and protein kinase B/Ak t. In these cells, GH stimulates the expression of IGF-I and two members of the suppressors of cytokine signaling family, cytokine-inducible SH2-conta ining protein and suppressor of cytokine signaling-2. Treatment of C2C12 my oblasts with either the MAPK kinase inhibitor PD98059 or the PI3K inhibitor wortmannin results in higher levels of GH-induced IGF-I and suppressor of cytokine signaling-2 mRNA expression, suggesting that activation of MAPK an d PI3K pathways has an inhibitory role in IGF-I and suppressor of cytokine signaling-2 gene regulation. Therefore, C2C12 cells provide the first in vi tro model system to study various aspects of GH action in skeletal muscle.