Compartment-specific remodeling of skeletal muscle in Duchenne muscular dystrophy

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.