Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice
Darko Bosnakovski, … , Dawn A. Lowe, Michael Kyba
Darko Bosnakovski, … , Dawn A. Lowe, Michael Kyba
Published April 6, 2020
Citation Information: J Clin Invest. 2020;130(5):2465-2477. https://doi.org/10.1172/JCI133303.
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Research Article Muscle biology Neuroscience

Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is caused by loss of repression of the DUX4 gene; however, the DUX4 protein is rare and difficult to detect in human muscle biopsies, and pathological mechanisms are obscure. FSHD is also a chronic disease that progresses slowly over decades. We used the sporadic, low-level, muscle-specific expression of DUX4 enabled by the iDUX4pA-HSA mouse to develop a chronic long-term muscle disease model. After 6 months of extremely low sporadic DUX4 expression, dystrophic muscle presented hallmarks of FSHD histopathology, including muscle degeneration, capillary loss, fibrosis, and atrophy. We investigated the transcriptional profile of whole muscle as well as endothelial cells and fibroadiopogenic progenitors (FAPs). Strikingly, differential gene expression profiles of both whole muscle and, to a lesser extent, FAPs, showed significant overlap with transcriptional profiles of MRI-guided human FSHD muscle biopsies. These results demonstrate a pathophysiological similarity between disease in muscles of iDUX4pA-HSA mice and humans with FSHD, solidifying the value of chronic rare DUX4 expression in mice for modeling pathological mechanisms in FSHD and highlighting the importance FAPs in this disease.

Authors

Darko Bosnakovski, Ahmed S. Shams, Ce Yuan, Meiricris T. da Silva, Elizabeth T. Ener, Cory W. Baumann, Angus J. Lindsay, Mayank Verma, Atsushi Asakura, Dawn A. Lowe, Michael Kyba

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Figure 6

Genes affected in FAPs from the iDUX4pA-HSA mouse are enriched in DEG sets from patients with FSHD.

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Genes affected in FAPs from the iDUX4pA-HSA mouse are enriched in DEG se...
(A) Heatmap represents a clustering of differentially expressed genes in FAP (CD45–CD31–Pdgfrα+) FACS-sorted cells from control and iDUX4pA-HSA mice after 10 days and 6 months induction with doxycycline (625 mg/kg). (B) Venn diagram and KEGG pathway analyses on the samples presented at A. (C) Gene set enrichment analysis (GSEA) of differentially expressed genes (DEGs) in PDGFRα+ cells isolated from mice induced for 10 days and DEGs identified in FSHD biopsies in 2 different studies (24, 25). (D) GSEA in DEGs identified in PDGFRα+ cells from mice induced for 6 months and FSHD samples. (E) Venn diagrams for core-enriched genes identified in GSEA analyses presented in C and D. (F) Venn diagram presents the overlap of core-enriched genes identified in FSHD biopsies (Tasca, ref. 24, and Wang, ref. 25, data sets) and DEGs from whole muscle from mice treated with doxycycline for 2 and 16 weeks and FAPs isolated from acute (10 days) and chronic (6 months) induced mice. Genes that were identified that were differentially expressed in FAPs from the FSHD animal model are highly enriched in DEG sets from muscle of patients with FSHD. (G) The DUX4 score shows no enrichment of DUX4 early target genes in PDGFRα cells from iDUX4pA-HSA mice.