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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autophagy / genetics
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Cell Cycle Proteins
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DNA Repair
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Female
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Forkhead Box Protein O1
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Forkhead Box Protein O3
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Forkhead Transcription Factors / deficiency
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Forkhead Transcription Factors / genetics*
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Gene Expression Regulation
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Gene Regulatory Networks
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Gluconeogenesis / genetics
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Lysosomes / metabolism
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Lysosomes / pathology
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Male
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Mice
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Mice, Knockout
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / pathology
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Muscular Atrophy / genetics*
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Muscular Atrophy / metabolism
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Muscular Atrophy / pathology
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Proteasome Endopeptidase Complex / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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Transcription, Genetic*
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Ubiquitin / genetics*
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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Unfolded Protein Response / genetics
Substances
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Cell Cycle Proteins
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Forkhead Box Protein O1
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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FoxO4 protein, mouse
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Foxo1 protein, mouse
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Ubiquitin
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Ubiquitin-Protein Ligases
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mTOR protein, mouse
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Proteasome Endopeptidase Complex