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FIGURE 7 5.3.3 ROS-mediated activation of FoxO and initiation of protein degradation programs The forkhead box O (FoxO) transcription factors, particularly FoxO1 and FoxO3 in skeletal muscle, play a central role in regulating proteolysis by activating both the ubiquitin-proteasome system (UPS) and autophagy-lysosome system (ALS) ( Besides classical targets, FoxOs also regulate noncanonical E3 ligases such as MUSA1, FBXO31, SMART (FBXO21), and Itch, with FoxO3 as the dominant factor ( In vivo studies show that muscle-specific triple knockout of FoxO1/3/4 abolishes the induction of 29 atrogenes-including E3 ligases, autophagy mediators, deubiquitinases (e.g., USP14), and proteasome subunits (e.g., Psmd11)-under catabolic stimuli, preserving muscle mass and strength (Sanchez et al., 2014)

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