Spatial transcriptomics reveal markers of histopathological changes in Duchenne muscular dystrophy mouse models

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, leading to lack of dystrophin. Chronic muscle damage eventually leads to histological alterations in skeletal muscles. The identification of genes and cell types driving tissue remodeling is a key step to develop effective therapies. Here we use spatial transcriptomics in two DMD mouse models differing in disease severity to identify gene expression signatures underlying skeletal muscle pathologies and directly link this to the muscle histology. Deconvolution analysis allowed the identification of cell types contributing to histological alterations. We show how the expression of specific genes is enriched in areas of muscle regeneration ( Myl4 , Sparc , Hspg2 ), fibrosis ( Vim , Fn1 , Thbs4 ) and calcification ( Bgn , Ctsk , Spp1 ). Finally, our analysis of differentiation dynamics in the severely affected D2-mdx muscle shows a subset of the muscle fibers are predicted to become affected in its future state. Genes associated with tissue remodeling could enable to design new diagnostic and therapeutic strategies for DMD.

Authors 6

1. Laura G.M. Heezen Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Dept. of Human Genetics, Leiden University Medical Center, The Netherlands

2. Tamim Abdelaal Aachen Department of Radiology, Leiden University Medical Center Leiden Computational Biology Center

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Delft Bioinformatics Lab, Delft University of Technology, The Netherlands

   Department of Radiology, Leiden University Medical Center, The Netherlands

   Leiden Computational Biology Center, Leiden University Medical Center, The Netherlands

3. Maaike van Putten Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Dept. of Human Genetics, Leiden University Medical Center, The Netherlands

4. Annemieke M Aartsma-Rus Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Dept. of Human Genetics, Leiden University Medical Center, The Netherlands

5. Ahmed Essam Mahfouz Aachen Department of Human Genetics Leiden Computational Biology Center

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Delft Bioinformatics Lab, Delft University of Technology, The Netherlands

   Dept. of Human Genetics, Leiden University Medical Center, The Netherlands

   Leiden Computational Biology Center, Leiden University Medical Center, The Netherlands

6. Pietro Spitali corresponding Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Dept. of Human Genetics, Leiden University Medical Center, The Netherlands