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 5

Fibrosis and FAP infiltration in DUX4 affected muscle.

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Fibrosis and FAP infiltration in DUX4 affected muscle. (A) Representativ...
(A) Representative FACS profiles for CD45–CD31–Itga7–Pdgfrα+, CD45–CD31–Itga7–Sca1+, and CD45–CD31–Itga7+VCAM+ cells in skeletal muscle from iDUX4pA-HSA mice induced with various concentration of doxycycline for 3 months. Doxycycline was continuously administrated to the mice through custom-made food containing dilutions of doxycycline. (B) Summary of FACS analyses on the cells presented in A. Data are shown as mean ± SEM; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 1-way ANOVA, n = 4. (C) Representative images of Sirius red/Fast green staining of quadriceps from WT and iDUX4pA-HSA mice at 6 months. Scale bar: 100 μm. (D) Quantification of deposition of fibrous tissue in the muscle presented in C. SRFG, Sirius Red/Fast Green. Data are shown as mean ± SEM; ***P < 0.001 by t test, n = 4.