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

Giulia Milan, Vanina Romanello, Francesca Pescatore, Andrea Armani, Ji Hye Paik, Laura Frasson, Anke Seydel, Jinghui Zhao, Reimar Abraham, Alfred L. Goldberg, Bert Blaauw, Ronald A. DePinho, Marco Sandri

Research output: Contribution to journalArticlepeer-review

473 Scopus citations

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.

Original languageEnglish (US)
Article number6670
JournalNature communications
Volume6
DOIs
StatePublished - Apr 10 2015

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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