Publications

Dernière publication 25/03/2022

Duchenne muscular dystrophy trajectory in R-DMDdel52 preclinical rat model ident

Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disorder caused by mutations in the Dystrophin gene and for which there is currently no...

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    [title] => Duchenne muscular dystrophy trajectory in R-DMDdel52 preclinical rat model ident
    [paragraph] => Duchenne muscular dystrophy trajectory in R-DMDdel52 preclinical rat model identifies COMP as biomarker of fibrosis
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Authors
Taglietti, V., Kefi, K., Bronisz-Budzy_ska, I. et al.

 Lab
Univ Paris-Est Creteil, INSERM, Creteil, France
Journal
Acta Neuropathologica Communications
Abstract
Duchenne 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.
BIOSEB Instruments Used
Grip strength test (BIO-GS3)

Keywords/Topics
Myopathie de Duchenne
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Une méthode simple pour quantifier objectivement la force musculaire des rats et souris et l'effet de drogues, toxines, maladies musculaires (ex: myopathie) et neurodégénératives. Cette mesure de force est souvent employée en association avec le test de coordination motrice ROTAROD: un sujet présentant une coordination normale montrera des résultats médiocres en cas de faible force musculaire. Un must pour vos recherches sur l'activité, la coordination et le contrôle musculaire: particulièrement utile pour vos études sur les maladies de Parkinson et Huntington.
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