The balance between protein synthesis and degradation determines whether muscles hypertrophy or atrophy. The balance between protein synthesis and degradation determines whether muscles hypertrophy or atrophy. With hypertrophy, protein synthesis exceeds degradation because the phosphatidylinositol 3 kinase (PI3-K)/Akt pathway stimulates protein synthesis and phosphorylates the FoxO transcription factors that stimulate protein degradative processes. In diseases that suppress insulin/IGF-1 signaling, the PI3-K/Akt pathway is depressed, leading to decreased protein synthesis and FoxO phosphorylation. This allows FoxO to stimulate the expression of the E3 enzymes atrogin-1 and muscle ring finger-1 (MuRF-1) and protein degradation. Another stimulus, inflammatory cytokines such as TNF-α, increases the activation of NF-κB, leading to expression of the E3 enzyme MuRF-1 and protein degradation. Illustration by Josh Gramling—Gramling Medical Illustration. Stewart H. Lecker et al. JASN 2006;17:1807-1819 ©2006 by American Society of Nephrology