Stimulation of EGFR signaling in fibro-adipogenic precursors decreases adipogenesis in Duchenne muscular dystrophy
Abstract
Background: Duchenne Muscular Dystrophy (DMD) is characterized by the formation of fibrosis and fat deposits that progressively replace muscle fibers, resulting in the loss of muscle function. Both fibrosis and adipogenesis are operated by fibroadipogenic precursors (FAPs), but the molecular regulation and interactions between the two processes are not fully understood. Methods: Adipogenesis was investigated in vivo in the D2-mdx mouse, and in vitro using FAPs isolated from WT (DBA/2) and D2-mdx muscles. Epithelial Growth Factor (EGF) was overexpressed in the D2-mdx muscle via electroporation of an expression plasmid. Results: We found that the D2-mdx gastrocnemius muscle showed fat deposition from 10 weeks of age and increased until 18 weeks of age, coinciding with fibrosis. Fat deposition was exclusively found within fibrotic areas. In vitro, D2-mdx FAPs proliferated more, and were more prone to adipogenesis than WT FAPs. Cells from both genotypes showed equal fibrogenesis. Analysis of normal muscle snRNAseq data showed that the Epithelial Growth Factor Receptor (EGFR) was primarily expressed by FAPs. Both EGFR expression and EGFR-phosphorylation were decreased in D2-mdx FAPs as compared with WT FAPs. Stimulating FAPs with EGF decreased adipogenesis, more efficiently in D2-mdx FAPs than in WT FAPs. However, EGF stimulation of EGFR had no effect on their fibrogenic differentiation. Finally, in vivo overexpression of EGF in D2-mdx gastrocnemius muscles reduced both adipogenesis and fibrosis, and was associated with an increased muscle force. Conclusions: In a DMD context, FAPs are more likely to differentiate into adipocytes than in normal muscle, which is associated with decreased EGFR signaling. Stimulating EGFR signaling decreased adipogenesis in vitro and fat deposition in vivo. The impact of EGFR signaling on fibrogenesis is unclear, the reduced fibrosis observed in vivo may be due to indirect mechanisms. This study identifies EGFR signaling as a new molecular mechanism for controlling adipogenesis in skeletal muscle FAPs.
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BibTeX
@article{guillemaud2026stimulation,
title = {{Stimulation of EGFR signaling in fibro-adipogenic precursors decreases adipogenesis in Duchenne muscular dystrophy}},
author = {Jules Guillemaud and Georgiana Panci and Aurélie Fessard and Léa Delivry and William Jarassier and Rémi Mounier and Julien Gondin and Stéphanie Gobert and Bénédicte Chazaud},
journal = {Skeletal Muscle},
year = {2026},
month = nov,
doi = {10.1186/s13395-026-00429-2},
url = {https://hal.science/hal-05850090v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Stimulation of EGFR signaling in fibro-adipogenic precursors decreases adipogenesis in Duchenne muscular dystrophy
AU - Jules Guillemaud
AU - Georgiana Panci
AU - Aurélie Fessard
AU - Léa Delivry
AU - William Jarassier
AU - Rémi Mounier
AU - Julien Gondin
AU - Stéphanie Gobert
AU - Bénédicte Chazaud
PY - 2026
DA - 2026/11/03
JO - Skeletal Muscle
DO - 10.1186/s13395-026-00429-2
UR - https://hal.science/hal-05850090v1
AB - Background: Duchenne Muscular Dystrophy (DMD) is characterized by the formation of fibrosis and fat deposits that progressively replace muscle fibers, resulting in the loss of muscle function. Both fibrosis and adipogenesis are operated by fibroadipogenic precursors (FAPs), but the molecular regulation and interactions between the two processes are not fully understood. Methods: Adipogenesis was investigated in vivo in the D2-mdx mouse, and in vitro using FAPs isolated from WT (DBA/2) and D2-mdx muscles. Epithelial Growth Factor (EGF) was overexpressed in the D2-mdx muscle via electroporation of an expression plasmid. Results: We found that the D2-mdx gastrocnemius muscle showed fat deposition from 10 weeks of age and increased until 18 weeks of age, coinciding with fibrosis. Fat deposition was exclusively found within fibrotic areas. In vitro, D2-mdx FAPs proliferated more, and were more prone to adipogenesis than WT FAPs. Cells from both genotypes showed equal fibrogenesis. Analysis of normal muscle snRNAseq data showed that the Epithelial Growth Factor Receptor (EGFR) was primarily expressed by FAPs. Both EGFR expression and EGFR-phosphorylation were decreased in D2-mdx FAPs as compared with WT FAPs. Stimulating FAPs with EGF decreased adipogenesis, more efficiently in D2-mdx FAPs than in WT FAPs. However, EGF stimulation of EGFR had no effect on their fibrogenic differentiation. Finally, in vivo overexpression of EGF in D2-mdx gastrocnemius muscles reduced both adipogenesis and fibrosis, and was associated with an increased muscle force. Conclusions: In a DMD context, FAPs are more likely to differentiate into adipocytes than in normal muscle, which is associated with decreased EGFR signaling. Stimulating EGFR signaling decreased adipogenesis in vitro and fat deposition in vivo. The impact of EGFR signaling on fibrogenesis is unclear, the reduced fibrosis observed in vivo may be due to indirect mechanisms. This study identifies EGFR signaling as a new molecular mechanism for controlling adipogenesis in skeletal muscle FAPs.
SN - 2044-5040
ER -