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

Author

Listed:
  • Giulia Milan

    (Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy)

  • Vanina Romanello

    (Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy)

  • Francesca Pescatore

    (Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy
    University of Padova)

  • Andrea Armani

    (Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy)

  • Ji-Hye Paik

    (Weill Cornell Medical College)

  • Laura Frasson

    (Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy)

  • Anke Seydel

    (Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy)

  • Jinghui Zhao

    (Harvard Medical School)

  • Reimar Abraham

    (U3 Pharma GmbH)

  • Alfred L. Goldberg

    (Harvard Medical School)

  • Bert Blaauw

    (University of Padova)

  • Ronald A. DePinho

    (University of Texas MD Anderson Cancer Center)

  • Marco Sandri

    (Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy
    University of Padova
    Institute of Neuroscience, Consiglio Nazionale delle Ricerche
    McGill University)

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.

Suggested Citation

  • 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, 2015. "Regulation of autophagy and the ubiquitin–proteasome system by the FoxO transcriptional network during muscle atrophy," Nature Communications, Nature, vol. 6(1), pages 1-14, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7670
    DOI: 10.1038/ncomms7670
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    Cited by:

    1. Jean-Philippe Leduc-Gaudet & Anais Franco-Romero & Marina Cefis & Alaa Moamer & Felipe E. Broering & Giulia Milan & Roberta Sartori & Tomer Jordi Chaffer & Maude Dulac & Vincent Marcangeli & Dominique, 2023. "MYTHO is a novel regulator of skeletal muscle autophagy and integrity," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Takayoshi Sasako & Toshihiro Umehara & Kotaro Soeda & Kazuma Kaneko & Miho Suzuki & Naoki Kobayashi & Yukiko Okazaki & Miwa Tamura-Nakano & Tomoki Chiba & Domenico Accili & C. Ronald Kahn & Tetsuo Nod, 2022. "Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Haiwen Li & Peipei Wang & Chen Zhang & Yuanbojiao Zuo & Yuan Zhou & Renzhi Han, 2023. "Defective BVES-mediated feedback control of cAMP in muscular dystrophy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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