Spatial transcriptomics maps region and isoform specific brain alterations in mdx and mdx4cv models of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is accompanied by cognitive and neurodevelopmental difficulties. To investigate how the loss of different dystrophin isoforms affects gene expression across brain regions, we performed spatial transcriptomics on brains from mdx and mdx4cv mouse models (lacking Dp427 or Dp427+Dp140 respectively) and healthy controls aged 2 weeks. Both dystrophic models showed transcriptional changes converging on myelin and oligodendrocyte biology and oxidative phosphorylation, but with distinct regional patterns. In mdx mice, myelin genes were upregulated in the amygdala and hippocampus and downregulated in fiber tract regions, while mitochondrial genes were upregulated in most regions but downregulated in the thalamus and isocortex. In mdx4cv mice, myelin genes were broadly upregulated and mitochondrial genes downregulated across almost all regions. Direct comparison between mdx and mdx4cv mice demonstrated that the additional loss of Dp140 expanded localized myelin upregulation across the brain and shifts the mitochondrial response toward widespread downregulation. These differences in regional changes between the mouse models is in line with their dystrophin isoform(s) loss. Our findings provide a molecular basis for the brain-related impairments of DMD and a foundation for future therapeutic studies.