Figure 3 Signaling pathway with UPS-related muscle wasting in cardiac cachexiaIn cardiac cachexia, muscle wasting is driven by disruptions in the anabolic-catabolic balance. (1) During anabolic phases, IGF1 binds to the both the IGF-1 receptor (IGF1R) and the insulin receptor (IR), leading to the phosphorylation of insulin receptor substrate 1 (IRS1) and activation of the PI3K-Akt-mTOR signaling pathway, which promotes protein synthesis. However, this anabolic signaling is often impaired in CHF. (2) During catabolic phases, myostatin, pro-inflammatory cytokines such as TNFα, IL-1, and IL-6, Ang-II, and glucocorticoids bind to their respective receptors and initiate the transcription of atrophy-related genes Trim63 and Fbxo32 via the NF-κB, Foxo, and SMAD signaling pathways. This results in increased expression of E3 ubiquitin ligases, MuRF1, and MAFbx/atrogin-1, leading to protein degradation through UPS activation. Created with Microsoft® Excel® 2021MSO (version 2407 Build 16.0.17830.20166).