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

TitleRegulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy.
Publication TypeJournal Article
Year of Publication2015
AuthorsMilan G, Romanello V, Pescatore F, Armani A, Paik J-H, Frasson L, Seydel A, Zhao J, Abraham R, Goldberg AL, Blaauw B, DePinho RA, Sandri M
JournalNat Commun
Date Published2015 Apr 10
KeywordsAnimals, Autophagy, Cell Cycle Proteins, DNA Repair, Female, Forkhead Box Protein O1, Forkhead Box Protein O3, Forkhead Transcription Factors, Gene Expression Regulation, Gene Regulatory Networks, Gluconeogenesis, Lysosomes, Male, Mice, Mice, Knockout, Muscle, Skeletal, Muscular Atrophy, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-akt, Signal Transduction, TOR Serine-Threonine Kinases, Transcription, Genetic, Ubiquitin, Ubiquitin-Protein Ligases, Unfolded Protein Response

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.

Alternate JournalNat Commun
PubMed ID25858807
PubMed Central IDPMC4403316
Grant ListTCR09003 / / Telethon / Italy
Related Faculty: 
Ji-Hye Paik, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700