The insulin-like growth factor-1-phosphotidylinositol-3-kinase-protein kinase-B serine/threonine kinase-forkhead box-O pathway. (a) Increased insulin-like growth factor-1 (IGF-1) activates phosphotidylinositol-3-kinase (PI3K), leading to phosphorylation of protein kinase-B serine/threonine kinase (Akt) and forkhead box-O (Foxo). Phosphorylated Foxo is sequestered within the cytoplasm and prevents its nuclear translocation and atrogin-1 (muscle atrophy F-box (MAFbox)) activation. Phosphorylated Akt also activates mammalian target of rapamycin (mTOR) and p70Sk, resulting in increased protein synthesis. (b) Suppression of IGF-1 with controlled mechanical ventilation-induced diaphragm muscle inactivity deactivates Akt, leading to nuclear translocation of Foxo, which then activates atrogin-1 and other atrogenes resulting in increased proteolysis. Reprinted from Cell, 117, Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL, Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy, 14 Pages, Copyright (2004), with permission from Elsevier .