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

Nat Commun. 2015 Apr 10;6:6670. doi: 10.1038/ncomms7670.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Proteasome Endopeptidase Complex