25 | Target adipogenic progenitors to cure Duchenne muscular dystrophy

Luca Sali¹, B. Periou², A. Cojocaru¹, E. Giry¹, G. Severa², L. Giordani³, V. Taglietti¹, E. Malfatti^1|2 | ¹Univ. Paris-Est Créteil, INSERM, U955 IMRB, Créteil, France; ²Assistance Publique-Hôpitaux de Paris, Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, Filnemus, Hôpital Henri Mondor, Créteil, France; European Reference Center for Neuromuscular Disorders, EURO-NMD, France; ³Sorbonne Université, INSERM UMRS 974, Association Institut de Myologie, Centre de Recherche en Myologie, Paris, France.

Abstract

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by mutations in the DMD gene, leading to the absence of dystrophin and progressive muscle degeneration. A hallmark of DMD pathology is the replacement of muscle fibers by fibrotic and adipose tissue, driven by aberrant activation of fibro-adipogenic progenitors (FAPs). These mesenchymal stromal cells, that physiologically support muscle regeneration, become dysregulated in DMD and contribute to pathological fat and fibrosis accumulation. This project places human biology at its core, leveraging a multi-omic strategy directly on patient muscle biopsies. Through single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics, we will characterize the heterogeneity of FAPs in DMD patients and identify molecular signatures associated with their adipogenic fate. This high-resolution profiling aims to uncover key regulators and exploitable pathways driving ectopic adipogenesis. In parallel, we will develop a drug screening using human primary FAPs and muscle stem cells, derived and expanded from both DMD patients and healthy controls. Candidate compounds emerging from omics-driven hypotheses will be tested in vitro and validated in vivo using the R-DMDdel52 rat model. By combining advanced omics directly on human tissue with functional pharmacological assays, this project aims to identify novel therapeutic targets to limit adipocyte accumulation and improve muscle preservation in DMD and related muscular diseases.