fig4

Figure 4. Overview of molecular regulators of proteostasis. Maintenance of the proteome, including synthesis of new proteins and degradation of old and damaged proteins, is dysregulated in both the failing heart and sarcopenic muscle. Signal transducers linking hormonal and nutritional changes to protein synthesis are conserved between the heart and peripheral muscle, including mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K) / protein kinase B (AKT), AMP-activated protein kinase, and mammalian target of rapamycin (mTOR). Signals promoting proteolysis include Forkhead box O (FoxO) proteins, which can promote transcription of F-box protein 32 (FBXO32) to increase expression of Atrogin-1 to activate the ubiquitin protease system (UPS). Similarly, activation of nuclear factor κB (NF-κB) triggers transcription of TRIM63 to drive Muscle RING-finger protein-1 (MuRF-1) expression and promote UPS. Kruppel-like factors (KLFs) are promoted by inactivity to inhibit protein synthesis.