Unraveling the spatial landscape of dystrophinopathies: a transcriptomic approach to Becker and Duchenne muscular dystrophies

Abstract

Dystrophinopathies are caused by pathogenic variants in the DMD gene, resulting in partial (Becker) or complete loss (Duchenne) of dystrophin. Becker (BMD) and Duchenne muscular dystrophy (DMD) are characterized by progressive muscle wasting, fatty replacement, fibrosis, and loss of function. To study histopathological changes, we used Visium spatial transcriptomics to profile skeletal muscle biopsies of patients affected by dystrophinopathy (n = 8) and healthy controls (n = 4). We estimated the proportion of cell types and their spatial localization across samples applying a deconvolution strategy using previously published single-nucleus RNA-sequencing data. We identified genes enriched in fat patches and cell types such as fibroadipogenic progenitors (FAPs) in areas of active pathology. Using expression data of ligand–receptor pairs, we highlight cell–cell communications leading to fibrotic and adipogenic lesions. Finally, analysis of gene expression gradients in areas of adjacent muscle and fat, allowed the identification of genes associated with muscle areas committed to becoming fat. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.