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COUP-TFII regulates satellite cell function and muscular dystrophy
Xin Xie, … , Sophia Y. Tsai, Ming-Jer Tsai
Xin Xie, … , Sophia Y. Tsai, Ming-Jer Tsai
Published September 12, 2016
Citation Information: J Clin Invest. 2016;126(10):3929-3941. https://doi.org/10.1172/JCI87414.
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Research Article Stem cells

COUP-TFII regulates satellite cell function and muscular dystrophy

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Abstract

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle-wasting disease caused by mutations in the dystrophin gene. Although dystrophin deficiency in myofiber triggers the disease’s pathological changes, the degree of satellite cell (SC) dysfunction defines disease progression. Here, we have identified chicken ovalbumin upstream promoter–transcription factor II (COUP-TFII) hyperactivity as a contributing factor underlying muscular dystrophy in a dystrophin-deficient murine model of DMD. Ectopic expression of COUP-TFII in murine SCs led to Duchenne-like dystrophy in the muscles of control animals and exacerbated degenerative myopathies in dystrophin-deficient mice. COUP-TFII–overexpressing mice exhibited regenerative failure that was attributed to deficient SC proliferation and myoblast fusion. Mechanistically, we determined that COUP-TFII coordinated a regenerative program through combined regulation of multiple promyogenic factors. Furthermore, inhibition of COUP-TFII preserved SC function and counteracted the muscle weakness associated with Duchenne-like dystrophy in the murine model, suggesting that targeting COUP-TFII is a potential treatment for DMD. Together, our findings reveal a regulatory role of COUP-TFII in the development of muscular dystrophy and open up a potential therapeutic opportunity for managing disease progression in patients with DMD.

Authors

Xin Xie, Sophia Y. Tsai, Ming-Jer Tsai

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Figure 3

Impaired muscle recovery in COUP-TFII–transgenic mice suffering acute injury.

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Impaired muscle recovery in COUP-TFII–transgenic mice suffering acute
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(A) Representative H&E-stained TA muscles showed the course of regeneration in control and COUP-TFII OE mice at different time points after injury. Images are representative of 4 animals for each genotype at different time points. (B) Histograms represent the frequency distribution across TA muscles according to the cross-sectional area at post-damage day 12 (n = 6). (C and D) Two days after injury, TA muscle were pulsed with BrdU for 2 hours prior to tissue harvesting and were stained with BrdU Ab. Percentage of BrdU+ cells over total nuclei in control (n = 5) and COUP-TFII OE (n = 6) mice. (E and F) Representative images of PAX7 immunostaining and quantitative measurement of PAX7+ cells 5 days after muscle damage (n = 6). (G) Immunostaining for MHC, eMHC, and Myc 12 days after chemical injection. (H) TA muscles were examined 2 months after CTX-induced injury. Data are representative of 3 independent experiments. Scale bars: 50 μm. **P < 0.01 and ***P < 0.001, by 2-tailed Student’s t test. Data represent the mean ± SEM.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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