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YTHDF2 governs muscle size through a targeted modulation of proteostasis

Author

Listed:
  • Christopher J. Gilbert

    (The Ohio State University
    Brown University)

  • Charles P. Rabolli

    (The Ohio State University
    Brown University)

  • Volha A. Golubeva

    (The Ohio State University)

  • Kristina M. Sattler

    (The Ohio State University)

  • Meifang Wang

    (University of Missouri
    University of Missouri)

  • Arsh Ketabforoush

    (University of Missouri
    University of Missouri)

  • W. David Arnold

    (University of Missouri
    University of Missouri
    University of Missouri
    University of Missouri)

  • Christoph Lepper

    (The Ohio State University)

  • Federica Accornero

    (The Ohio State University
    Brown University)

Abstract

The regulation of proteostasis is fundamental for maintenance of muscle mass and function. Activation of the TGF-β pathway drives wasting and premature aging by favoring the proteasomal degradation of structural muscle proteins. Yet, how this critical post-translational mechanism is kept in check to preserve muscle health remains unclear. Here, we reveal the molecular link between the post-transcriptional regulation of m6A-modified mRNA and the modulation of SMAD-dependent TGF-β signaling. We show that the m6A-binding protein YTHDF2 is essential to determining postnatal muscle size. Indeed, muscle-specific genetic deletion of YTHDF2 impairs skeletal muscle growth and abrogates the response to hypertrophic stimuli. We report that YTHDF2 controls the mRNA stability of the ubiquitin ligase ASB2 with consequences on anti-growth gene program activation through SMAD3. Our study identifies a post-transcriptional to post-translational mechanism for the coordination of gene expression in muscle.

Suggested Citation

  • Christopher J. Gilbert & Charles P. Rabolli & Volha A. Golubeva & Kristina M. Sattler & Meifang Wang & Arsh Ketabforoush & W. David Arnold & Christoph Lepper & Federica Accornero, 2024. "YTHDF2 governs muscle size through a targeted modulation of proteostasis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46546-8
    DOI: 10.1038/s41467-024-46546-8
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    References listed on IDEAS

    as
    1. Federica Accornero & Tobias G. Schips & Jennifer M. Petrosino & Shan-Qing Gu & Onur Kanisicak & Jop H. Berlo & Jeffery D. Molkentin, 2017. "BEX1 is an RNA-dependent mediator of cardiomyopathy," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    2. Hao Du & Ya Zhao & Jinqiu He & Yao Zhang & Hairui Xi & Mofang Liu & Jinbiao Ma & Ligang Wu, 2016. "YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex," Nature Communications, Nature, vol. 7(1), pages 1-11, November.
    3. Jennifer M. Petrosino & Scott A. Hinger & Volha A. Golubeva & Juan M. Barajas & Lisa E. Dorn & Chitra C. Iyer & Hui-Lung Sun & W. David Arnold & Chuan He & Federica Accornero, 2022. "The m6A methyltransferase METTL3 regulates muscle maintenance and growth in mice," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
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