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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 6670 (Apr 10 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 25858807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Forkhead Box Protein O1
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• FoxO3 protein, mouse
• FoxO4 protein, mouse
• Foxo1 protein, mouse
• Ubiquitin
• Ubiquitin-Protein Ligases
• mTOR protein, mouse
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Proteasome Endopeptidase Complex

Topics

• Animals
• Autophagy (genetics)
• Cell Cycle Proteins
• DNA Repair
• Female
• Forkhead Box Protein O1
• Forkhead Box Protein O3
• Forkhead Transcription Factors (deficiency, genetics)
• Gene Expression Regulation
• Gene Regulatory Networks
• Gluconeogenesis (genetics)
• Lysosomes (metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• Muscle, Skeletal (metabolism, pathology)
• Muscular Atrophy (genetics, metabolism, pathology)
• Proteasome Endopeptidase Complex (metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Transcription, Genetic
• Ubiquitin (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Unfolded Protein Response (genetics)