# YTHDF2 governs muscle size through a targeted modulation of proteostasis

## TL;DR

This study shows how the protein YTHDF2 helps control muscle size by regulating RNA modifications and protein degradation.

## Contribution

The study identifies a novel post-transcriptional mechanism involving YTHDF2 and m6A-modified mRNA in regulating muscle growth and proteostasis.

## Key findings

- YTHDF2 is essential for postnatal muscle growth and response to hypertrophic stimuli.
- YTHDF2 regulates mRNA stability of ubiquitin ligase ASB2, affecting anti-growth gene activation via SMAD3.
- The study reveals a post-transcriptional to post-translational mechanism coordinating muscle gene expression.

## 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.

This study highlights the role of YTHDF2, a protein that recognizes m6A-modified RNA, in determining muscle size. The authors show a post-transcriptional mechanism regulating muscle catabolism and growth, prompting interest to address muscle wasting.