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

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Version 2 2024-06-13, 14:40
Version 1 2021-09-29, 08:23
journal contribution
posted on 2024-06-13, 14:40 authored by D Bosnakovski, AS Shams, C Yuan, MT da Silva, ET Ener, CW Baumann, AJ Lindsay, M Verma, A Asakura, DA Lowe, M Kyba
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

History

Journal

Journal of Clinical Investigation

Volume

130

Pagination

2465-2477

Location

Ann Arbor, Mich.

Open access

  • Yes

ISSN

0021-9738

eISSN

1558-8238

Language

eng

Publication classification

C1 Refereed article in a scholarly journal

Issue

5

Publisher

American Society for Clinical Investigation