Duchenne muscular dystrophy trajectory in R-DMDdel52 preclinical rat model identifies COMP as biomarker of fibrosis

AbstractDuchenne muscular dystrophy (DMD) is a fatal muscle-wasting disorder caused by mutations in the Dystrophin gene and for which there is currently no cure. To bridge the gap between preclinical and therapeutic evaluation studies, we have generated a rat model for DMD that carries an exon 52 deletion (R-DMDdel52) causing a complete lack of dystrophin protein. Here we show that R-DMDdel52 animals recapitulated human DMD pathophysiological trajectory more faithfully than the mdx mouse model. We report that R-DMDdel52 rats displayed progressive and severe skeletal muscle loss associated with fibrotic deposition, fat infiltration and fibre type switch. Early fibrosis was also apparent in the cardiac muscle. These histological modifications led to severe muscle, respiratory and cardiac functional impairments leading to premature death around 1 year. Moreover, DMD muscle exhibited systemic inflammation with a mixed M1/M2 phenotype. A comparative single cell RNAseq analysis of the diaphragm muscle was performed, revealing cellular populations alteration and molecular modifications in all muscle cell types. We show that DMD fibroadipogenic progenitors produced elevated levels of cartilage oligomeric matrix protein, a glycoprotein responsible for modulating homeostasis of extracellular matrix, and whose increased concentration correlated with muscle fibrosis both in R-DMDdel52 rats and human patients. Fibrosis is a component of tissue remodelling impacting the whole musculature of DMD patients, at the tissue level but most importantly at the functional level. We therefore propose that this specific biomarker can optimize the prognostic monitoring of functional improvement of patients included in clinical trials.

Mots clés

Duchenne muscular dystrophy Long QT Preclinical modelling Skeletal muscle Translational medicine scRNAseq

Domaines

Sciences du Vivant [q-bio]

Fichier principal

40478_2022_Article_1355 Valentina RAT.pdf (16.72 Mo)

Origine	Fichiers éditeurs autorisés sur une archive ouverte

France Piétri-Rouxel : Connectez-vous pour contacter le contributeur

https://hal.science/hal-03828280

Soumis le : mardi 25 octobre 2022-16:44:32

Dernière modification le : mardi 17 septembre 2024-10:33:10

Archivage à long terme le : vendredi 27 janvier 2023-07:39:36

Dates et versions

hal-03828280 , version 1 (25-10-2022)

Identifiants

HAL Id : hal-03828280 , version 1
DOI : 10.1186/s40478-022-01355-2
PUBMED : 35468843
PUBMEDCENTRAL : PMC9036715

Citer

Valentina Taglietti, Kaouthar Kefi, Iwona Bronisz-Budzyńska, Busra Mirciloglu, Mathilde Rodrigues, et al.. Duchenne muscular dystrophy trajectory in R-DMDdel52 preclinical rat model identifies COMP as biomarker of fibrosis. Acta Neuropathologica Communications, 2022, 10 (1), ⟨10.1186/s40478-022-01355-2⟩. ⟨hal-03828280⟩

Exporter

BibTeX XML-TEI Dublin Core DC Terms EndNote DataCite

Collections

INSERM IMRB UPEC U974 SORBONNE-UNIVERSITE SU-MEDECINE ENVA ANR U974-E5 FRM

154 Consultations

26 Téléchargements