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

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

Author information

1
Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy.
2
1] Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy [2] Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
3
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
4
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
5
Department of Cancer Biology, U3 Pharma GmbH, Martinsried 82152, Germany.
6
Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
7
Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
8
1] Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy [2] Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy [3] Institute of Neuroscience, Consiglio Nazionale delle Ricerche, 35129 Padova, Italy [4] Department of Medicine, McGill University, Montreal, Quebec H3AoG4, Canada [5] Dulbecco Telethon Institute at Telethon Institute of Genetics and Medicine (TIGEM), 80131 Napoli, Italy.

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.

PMID:
25858807
PMCID:
PMC4403316
DOI:
10.1038/ncomms7670
[Indexed for MEDLINE]
Free PMC Article

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