YTHDF2 governs muscle size through a targeted modulation of proteostasis

Christopher J. Gilbert, Charles P. Rabolli, Volha A. Golubeva, Kristina M. Sattler, Meifang Wang, Arsh Ketabforoush, W. David Arnold, Christoph Lepper and Federica Accornero ()
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Christopher J. Gilbert: The Ohio State University
Charles P. Rabolli: The Ohio State University
Volha A. Golubeva: The Ohio State University
Kristina M. Sattler: The Ohio State University
Meifang Wang: University of Missouri
Arsh Ketabforoush: University of Missouri
W. David Arnold: University of Missouri
Christoph Lepper: The Ohio State University
Federica Accornero: The Ohio State University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46546-8

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