# Investigating the role of EGFR signalling in muscle dystrophies: implications for Duchenne muscular dystrophy

## TL;DR

This study explores how EGF signaling is altered in Duchenne muscular dystrophy and how it affects muscle cell behavior, offering insights for potential therapies.

## Contribution

The study identifies new molecular interactions of EGF and EFEMP1 in DMD muscle cells, revealing their distinct roles in fibrosis and myotube development.

## Key findings

- EFEMP1 is secreted by FAPs in DMD and increases myotube size without improving muscle strength.
- EGF promotes fibrotic differentiation in FAPs and smaller, proliferative myotubes in myoblasts.
- EGF activates EGFR and ErbB2, while EFEMP1 influences receptor heterodimerization to enhance EGF signaling.

## Abstract

The degeneration of the muscle in muscle dystrophies involves complex interactions among the different cell types. Here, we have used datasets from single-nuclei RNA sequencing (snRNAseq) of Duchenne Muscular Dystrophy (DMD) muscle samples to study the dysregulation of molecular pathways compared to healthy control muscle. We have observed that the epidermal growth factor (EGF) signaling is upregulated in DMD by an increase of the ligands EGF and EGF containing fibulin extracellular matrix protein 1 (EFEMP1). This study explores the role of EGF and EFEMP1 in FAPs and myoblasts in vitro. We provide evidence that EFEMP1 is secreted by FAPs in DMD and is mainly involved with increased myotube size but without enhancing muscle strength. Conversely, EGF enhances fibrotic differentiation in FAPs and promote smaller, proliferative myotubes in myoblasts, aligning with a fibrotic and dysfunctional muscle phenotype in DMD. The cellular differences from both ligands can be explained by the interactions with the receptor type, with EGF activating both EGFR and ErbB2, while EFEMP1 selectively maintained ErbB4 in an inactive state but promoting EGFR-ErbB2 and ErbB2-ErbB4 heterodimerization, potentially enhancing EGF signaling. Consequently, this study examinates the alteration of the EGF signalling in DMD and provides new molecular interactions in muscle that can be useful for targeted therapies of muscle degeneration.