# Investigating proteostasis in facioscapulohumeral muscular dystrophy

> **NIH NIH R21** · CHILDREN'S RESEARCH INSTITUTE · 2022 · $180,322

## Abstract

ABSTRACT
 Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disorder
caused by complex genetic and epigenetic mechanisms. Previous studies showed that transcription de-
repression of double homeobox protein 4 (DUX4) due to epigenetic changes in the D4Z4 region causes
FSHD. The epigenetic changes are caused by either contraction of the D4Z4 array from 11-150 repeat
units in unaffected individuals to 1-10 repeat units in roughly 95% of patients (FSHD1), or mutations in
epigenetic regulators of the D4Z4 region (FSHD2). The expression of DUX4 leads to downstream
molecular and cellular changes, which contribute to disease progression. Previous studies reported
defects in protein degradation process in FSHD, however what proteins are affected and whether
protein synthesis is affected is not clear. To study the dynamic changes in protein abundance in
affected muscle cells, the research team conducted a preliminary study using liquid chromatography -
tandem mass spectrometry in combination with metabolic labelling. The study identified distinct protein
profiles between the myoblasts from individuals affected by FSHD and their unaffected siblings. We
hypothesize that DUX4 expression is responsible for the disturbance of protein homeostasis, which
contributes to the downstream molecular and cellular defects observed in FSHD. In the proposed study,
we will first study the protein synthesis and degradation in immortalized FSHD myoblasts before and
after a DUX4-reducing treatment. In aim 2, we will validate the in vitro findings using a xenograft mouse
model. This project will discover proteins that are mis-regulated by degradative processes and synthetic
processes in FSHD, which may open new opportunities for therapeutic development. The findings will
also provide new insights of the disease mechanisms and evaluate the efficacy of a DUX4-reducing
treatment using antisense oligonucleotides targeting the DUX4.

## Key facts

- **NIH application ID:** 10430945
- **Project number:** 1R21AR080887-01
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** YI-WEN CHEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $180,322
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430945

## Citation

> US National Institutes of Health, RePORTER application 10430945, Investigating proteostasis in facioscapulohumeral muscular dystrophy (1R21AR080887-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10430945. Licensed CC0.

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