Single cell sequencing maps skeletal muscle cellular diversity as disease severity increases in dystrophic mouse models

Kholoud K Saleh; Haibin Xi; Corey Switzler; Emily Skuratovsky; Matthew A Romero; Peggie Chien; Devin Gibbs; Lily Gane; Michael R Hicks; Melissa J Spencer; April D Pyle

doi:10.1016/j.isci.2022.105415

Single cell sequencing maps skeletal muscle cellular diversity as disease severity increases in dystrophic mouse models

iScience. 2022 Oct 21;25(11):105415. doi: 10.1016/j.isci.2022.105415. eCollection 2022 Nov 18.

Authors

Kholoud K Saleh^{1

2

3}, Haibin Xi^{2

3}, Corey Switzler², Emily Skuratovsky⁴, Matthew A Romero^{2

3}, Peggie Chien^{2

3

5}, Devin Gibbs^{2

3

5}, Lily Gane^{2

3}, Michael R Hicks^{2

3}, Melissa J Spencer^{3

6}, April D Pyle^{1

2

3

5}

Affiliations

¹ Department of Molecular, Cellular and Integrative Physiology, University of California Los Angeles, Los Angeles, CA 90095, USA.
² Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA.
³ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁴ CIRM Bridges Program, California State University, Northridge, CA 91330, USA.
⁵ Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Neurology, University of California Los Angeles, CA 90095, USA.

Abstract

Duchenne muscular dystrophy (DMD) is caused by out-of-frame mutations in the DMD gene resulting in the absence of a functional dystrophin protein, leading to a devastating and progressive lethal muscle-wasting disease. Little is known about cellular heterogeneity as disease severity increases. Advances in single-cell RNA sequencing (scRNA-seq) enabled us to explore skeletal muscle-resident cell populations in healthy, dystrophic, and severely dystrophic mouse models. We found increased frequencies of activated fibroblasts, fibro-adipogenic progenitor cells, and pro-inflammatory macrophages in dystrophic gastrocnemius muscles and an upregulation of extracellular matrix genes on endothelial cells in dystrophic and severely dystrophic muscles. We observed a pronounced risk of clotting, especially in the severely dystrophic mice with increased expression of plasminogen activator inhibitor-1 in endothelial cells, indicating endothelial cell impairment as disease severity increases. This work extends our understanding of the severe nature of DMD which should be considered when developing single or combinatorial approaches for DMD.

Keywords: Animal physiology; Biological sciences; Cellular physiology; Natural sciences; Omics; Physiology; Transcriptomics.

Abstract

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