Insulin-like growth factor I-mediated skeletal muscle hypertrophy is characterized by increased mTORp70S6K signaling without increased Akt phosphorylation

Background—Insulin-like growth factor I (IGF-I) is an anabolic hormone that is known to induce skeletal muscle hypertrophy. However, the signaling pathways mediating IGF-I's hypertrophic effect in vivo are unknown. Method—The phosphorylation of 46 proteins was investigated by Kinetworks proteomic analysis in the gastrocnemius muscle of transgenic mice overexpressing IGF-I myosin light chain/muscle specific IGF-I (MLC/mIgf-I) and wild-type littermates. Results—In the hypertrophic muscle of MLC/mIgf-I mice, we observed increased phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1; 53 % increase), the mammalian target of rapamycin (mTOR; 112 % increase), and p70 S6 kinase (p70S6K) (254% increase) but no significant change in Akt phosphorylation (4 % decrease). Furthermore, we found reduced phosphorylation of MAP kinase kinase 1 and 2 (MEK1/2) (60 % decrease) and of mitogen-activated protein kinase kinases 3 and 6 (MKK3/6) (50 % decrease) in muscle from transgenic mice, suggesting that the hypertrophic and mitogenic effects of IGF-I are mediated via distinct signaling pathways in skeletal muscle and that inhibition of the mitogen-activated protei