Fig. 4

Catabolic pathways lead to muscle atrophy. During catabolic states, multiple intracellular signaling pathways are activated and stimulate muscle wasting via protein degradation, Ca2 + -dependent proteolysis system, and autophagy. These catabolic effects in muscle are mediated by specific transcription factors, such as FOXO proteins, NF-κB, and SMAD2 or SMAD3. The activation of these transcription factors results from extracellular stimuli or from stimulation of JAK-STAT signaling and a decrease in the PI3K-AKT-mTOR pathway. Together, these pathways accelerate protein degradation, proteolysis, and autophagy, leading to muscle atrophy. RAGE, receptor for advanced glycation end-product; HMGB1, high mobility group box 1; ActRIIb, activin type II receptor; IGF1, insulin-like growth factor 1; IGF1R, IGF1 receptor; PIF, proteolysis-inducing factor; PIFR, proteolysis-inducing factor receptor; FOXO, forkhead box protein O; and NF-kB, nuclear factor-κB