lindsay-transcriptionaland-2020.pdf (11.55 MB)
Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice
journal contribution
posted on 2020-05-01, 00:00 authored by D Bosnakovski, A S Shams, C Yuan, M T da Silva, E T Ener, C W Baumann, Angus Lindsay, M Verma, A Asakura, D A Lowe, M KybaFacioscapulohumeral 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 InvestigationVolume
130Issue
5Pagination
2465 - 2477Publisher
American Society for Clinical InvestigationLocation
Ann Arbor, Mich.Publisher DOI
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ISSN
0021-9738eISSN
1558-8238Language
engPublication classification
C1 Refereed article in a scholarly journalUsage metrics
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