# The Loss of HJV Aggravates Muscle Atrophy by Promoting the Activation of the TβRII/Smad3 Pathway

## TL;DR

This study shows that losing a protein called HJV worsens muscle atrophy by boosting a specific signaling pathway, suggesting HJV could be a target for treating muscle loss.

## Contribution

The study reveals a novel role for HJV in preventing muscle atrophy through its regulation of the TβRII/Smad3 pathway.

## Key findings

- Loss of HJV in muscle worsens disuse-induced atrophy and increases ubiquitin ligase expression.
- HJV deficiency enhances TβRII and p-Smad3 levels, promoting atrophy signaling.
- Reducing TβRII in HJV-deficient mice reverses atrophy and pathway activation.

## Abstract

Hemojuvelin (HJV) is a membrane-bound protein prominently expressed in the skeletal muscle, heart, and liver. Despite its established function in iron regulation, the specific role of HJV in muscle physiology and pathophysiology is not well understood. In this study, we explored the involvement of HJV in disuse-induced muscle atrophy and uncovered the potential mechanisms. Hindlimb unloading (HU) resulted in soleus muscle atrophy in wild type (WT) mice, accompanied by a significant decrease in HJV protein expression. The muscle-specific deletion of Hjv (MKO) exacerbated myofiber atrophy, which was associated with an increase in the expression of muscle ubiquitin ligases following HU. Furthermore, the expression of transforming growth factor-β type II receptor (TβRII) and the level of phosphorylated Smad3 (p-Smad3) were elevated after HU, and these effects were exacerbated in MKO mice. The knockdown of TβRII in the skeletal muscle of MKO mice mitigated myofiber atrophy and reversed the hyperactivation of the TβRII/Smad3 pathway induced by HU. Our findings demonstrate that the absence of HJV contributes to the activation of the TβRII/Smad3 signaling pathway and, consequently, the onset of myofiber atrophy in response to HU. Given its abundant expression in skeletal muscle, HJV emerges as a potential therapeutic target for muscle atrophy.