Mapping the unseen to uncover the unknown: spatial analysis of neuromuscular disorders

Dystrophinopathies are muscular dystrophies caused by mutations in the DMD gene, leading to loss or dysfunction of dystrophin, a protein essential for muscle stability and repair. This results in progressive muscle degeneration, as seen in Becker muscular dystrophy (BMD), a milder form with reduced or altered dystrophin, and Duchenne muscular dystrophy (DMD), a severe form with little to no functional dystrophin. This thesis investigates disease mechanisms and explores new research approaches to improve understanding and therapy development.<br>After introducing the pathology and relevant cell types, the thesis maps Dmd expression patterns in the brain using single-cell RNA sequencing and examines consequences of missing isoforms in DMD mouse models. It evaluates diffusion tensor MRI as a noninvasive alternative to muscle biopsies in BMD and pioneers the use of spatial transcriptomics to identify molecular markers and tissue changes in dystrophic muscle from mouse models and patients. These analyses reveal gene associations with pathology, tissue alterations such as fibrofatty infiltration, and cellular interactions in diseased muscle.<br>Overall, this work advances neuromuscular research by applying spatial transcriptomics to skeletal muscle, improving insight into disease pathology and assessing the need for invasive biopsies in BMD studies.<br>