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

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 spatial transcriptomics to profile skeletal muscle biopsies of BMD, DMD patients and healthy controls (N = 4 per group). We estimated the proportion of cell types and their spatial localization across samples applying a deconvolution strategy using single-nuclei RNA-sequencing data. We identified genes enriched in fat patches and cell types such as fibroadipogenic progenitor cells (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 become fat. Significance statementThis study investigates the cellular and molecular changes that occur in muscles affected by Becker and Duchenne muscular dystrophy (BMD and DMD). These diseases are caused by mutations in the DMD gene, leading to muscle degeneration and the replacement of muscle tissue with fibrotic and fatty tissue causative for an early death. By using spatial transcriptomics, the researchers analyzed muscle biopsies from BMD, DMD patients, and healthy controls. They identified specific genes and cell types, such as fibroadipogenic progenitor cells, that are involved in disease progression. The study also revealed how different cells communicate with each other to drive muscle degeneration and fat accumulation. These findings provide new insights into the mechanisms of disease and potential targets for future therapies.