Regulation of autophagy and the ubiquitin–proteasome system by the FoxO transcriptional network during muscle atrophy

TLDR

Stresses such as low nutrients, systemic inflammation, cancer or infections trigger a catabolic state with heightened muscle proteolysis and amino‑acid release to support liver gluconeogenesis and tissue protein synthesis, activating FoxO transcription factors. FoxO transcription factors orchestrate multiple stress‑response pathways, including the unfolded protein response, ROS detoxification, DNA repair, and translation. Muscle‑specific deletion of FoxOs protects against muscle loss by suppressing autophagy–lysosome and ubiquitin–proteasome activity, while FoxOs are necessary for Akt signaling but not mTOR, and they regulate ubiquitin ligases such as MUSA1 and SMART, underscoring their central role in coordinating stress‑response genes during catabolism.

Abstract

Abstract Stresses like low nutrients, systemic inflammation, cancer or infections provoke a catabolic state characterized by enhanced muscle proteolysis and amino acid release to sustain liver gluconeogenesis and tissue protein synthesis. These conditions activate the family of Forkhead Box (Fox) O transcription factors. Here we report that muscle-specific deletion of FoxO members protects from muscle loss as a result of the role of FoxOs in the induction of autophagy–lysosome and ubiquitin–proteasome systems. Notably, in the setting of low nutrient signalling, we demonstrate that FoxOs are required for Akt activity but not for mTOR signalling. FoxOs control several stress–response pathways such as the unfolded protein response, ROS detoxification, DNA repair and translation. Finally, we identify FoxO-dependent ubiquitin ligases including MUSA1 and a previously uncharacterised ligase termed SMART (Specific of Muscle Atrophy and Regulated by Transcription). Our findings underscore the central function of FoxOs in coordinating a variety of stress-response genes during catabolic conditions.