Year: 2024
Type: article
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 m 6 A-modified mRNA and the modulation of SMAD-dependent TGF-β signaling. We show that the m 6 A-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.
Source: Nature Communications
Authors: Christopher J. Gilbert, Charles P. Rabolli, Volha A. Golubeva, Kristina M. Sattler, Meifang Wang, Arsh Ketabforoush, W. David Arnold, Christoph Lepper, Federica Accornero
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: G1581437734, G1670106947, G1858189645, G1885445165, Mechanistic characterization of a new master regulator of cardiac virus infections, The role of YTHDF2 in postnatal cardiac growth and homeostasis, The Role of m6A Binding Protein YTHDF1 in Cardiac Homeostasis, G6834052811, Structured Illumination Microscope for high resolution imaging of cells and tissues, G7608207679, G8461815449, Regulation of Muscle Stem Cell Number via Paracrine Signaling, Cancer Center Support Grant, YTHDF3 as a critical regulator of cardiac function, Post-transcriptional regulation of cardiac hypertrophy
OpenAlex ID: W4392648336