Fig. 2

Scheme of the most common signaling pathways active in muscle during cancer cachexia. Several signaling pathways are activated by pro-inflammatory cytokines and tumuor-derived molecules. Protein degradation, through ubiquitin-proteosome pathways, can be activated by Insulin-like growth factor 1 (IGF1)/AKT signaling, Tumor Necrosis alpha (TNFα)/ nuclear factor-KB (NF-KB) signaling, Interleukin1 (IL-1)/NF-KB signaling, Interleukin 6 (IL6)/ Janus kinase (JAK)- signal transducer and activator of transcription proteins (STAT) signaling. Other pathways involved in the activation of the ubiquitin-proteosome pathway are p38/ CCAAT Enhancer Binding Protein Beta (C/EBPβ) and SMAD2/3 signaling induced by TNF-like weak inducer of apoptosis (TWEAK), Interferon gamma (INFγ) and transforming growth factor beta (TGFβ). These pathways all converge to activate the muscle specific ubiquitin ligase Atrogin1 and MURF1 (muscle atrophy F-box protein (MAFBX) and muscle RING finger-containing protein 1 (MURF1)) that ubiquitinate myofibrillar protein, inducing their degradation. The autophagy pathway can also be activated by STAT, SMAD2/3 p38 signaling pathways. Insulin-like growth factor 1 (IGF1), which normally stimulates protein synthesis via AKT and mTOR, is decreased during cachexia. These pathways are generally active in skeletal muscle. The activation of the TNFα/ NF-KB dependent ubiquitin–proteasome pathway is also active in cardiac muscle. Also, the autophagy pathway is activated in cardiac muscle