Compartment-specific remodeling of skeletal muscle in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) features progressive muscle degeneration with extensive remodeling of fiber type composition and metabolism. To circumvent the lack of regional heterogeneity from bulk or small biopsies studies, we employed spatial transcriptomics, metabolic enzyme profiling, immunohistochemistry, and quantitative fiber-type analysis to map the tibialis anterior (TA) in dystrophic (hDMDdel52/mdx) and control mice. DMD muscles exhibited disrupted metabolic compartmentalization, with reduced central oxidative regions and lower oxidative gene expression. Histology confirmed decreased oxidative enzyme activity and MYH2 expression, the most oxidative type 2 fiber. Analysis across TA, extensor digitorum longus, and soleus muscles revealed consistent MYH2 fiber loss within a mosaic of localized pathological states. Modeling interactions between anatomy and disease highlighted spatially restricted transcriptional programs involving extracellular matrix remodeling, cytoskeletal disruption, and immune infiltration, indicating compartment-specific pathology. This multi-modal, spatially resolved framework advances understanding of muscle remodeling and guides biomarker discovery and therapeutic strategies that account for regional heterogeneity.