# Investigating membrane repair capacity in facioscapulohumeral muscular dystrophy

> **NIH NIH R21** · CHILDREN'S RESEARCH INSTITUTE · 2021 · $223,125

## 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. However the cellular
mechanisms cause FSHD are not clear. In our preliminary studies we identified cell membrane repair
deficit in FSHD myoblasts in comparison to myoblasts from unaffected siblings. Moderate reduction of
DUX4 in the FSHD cells partially improved the repair capacity. This repair deficit was also observed in
skeletal muscle from an FSHD-like mouse model (FLExDUX4). It is known that FSHD myoblasts are
more susceptible to oxidative stress. While reactive oxygen species (ROS) regulation plays an
important role in sarcolemmal membrane repair, excessive or prolonged oxidative stress in cells lead to
membrane repair deficits. Our novel finding provides a plausible link between the molecular pathways
mis-regulated by DUX4 (e.g. oxidative stress) and the FSHD phenotype secondary to reduced
membrane repair capacity. The goal of the study is to further investigate the observed membrane repair
deficit and test the hypothesis that the membrane repair capacity is modulated by DUX4 levels in
myofibers. In aim 1, we will determine if DUX4 expression has a dose-dependent effect on sarcolemmal
repair deficit using skeletal muscle-specific inducible mouse model and an antisense oligonucleotide
that can modulate DUX4 expression in FLExDXU4 mice. Molecular mechanisms of repair deficits will
be investigated. In aim 2, we will evaluate the effect of DUX4 on sarcolemmal repair in FSHD patient
myofibers using a xenograft mouse model of FSHD. We will produce human myofibers and test their
sarcolemmal repair ability and determine whether AON-mediated knockdown of DUX4 affects the
membrane repair ability. The study will identify a novel mechanism, which links previously reported
molecular deficits to the disease phenotypes. In addition, the proposed study will determine whether
membrane repair can be an appropriate acute readout for therapeutic approaches that aim to reduce
DUX4, and its related pathways, in FSHD skeletal muscle.

## Key facts

- **NIH application ID:** 10108316
- **Project number:** 1R21HD103993-01
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** YI-WEN CHEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $223,125
- **Award type:** 1
- **Project period:** 2021-03-06 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10108316

## Citation

> US National Institutes of Health, RePORTER application 10108316, Investigating membrane repair capacity in facioscapulohumeral muscular dystrophy (1R21HD103993-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10108316. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*