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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 2

Analyses of the exacerbated dystrophic phenotypes in COUP-TFII OE mdx mice.

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Analyses of the exacerbated dystrophic phenotypes in COUP-TFII OE
      ...
(A) Representative H&E-stained diaphragm muscles from the indicated genotypes at 4 months of age. (B) Histogram indicates the percentage of central nuclei in the total nuclei in diaphragm muscles from mdx (n = 6) mice and COUP-TFII OE mdx (n = 8) mice. (C and D) Muscles were stained for eMHC, and eMHC+ fibers were measured as a fraction of total nuclei in mdx (n = 9) and COUP-TFII OE mdx (n = 7) strains. (E and F) Representative image and quantification of PAX7-expressing SCs in diaphragm sections in mdx (n = 8) and COUP-TFII OE mdx (n = 10) mouse strains. Arrowheads indicate the PAX7+ SCs. (G) Average mean value of lean body mass in mdx (n = 7) and COUP-TFII OE mdx (n = 6) mouse strains. (H) Representative x-ray image indicates severe kyphosis in dystrophic mice carrying the COUP-TFII minigene at 8 months of age. (I and J) Treadmill and grip tests for 6-month-old mdx (n = 12) and COUP-TFII OE mdx (n = 10) animals. Scale bars: 100 μm (A), 50 μm (C), 25 μm (E). **P < 0.01 and ***P < 0.001, by Student’s t test. Data represent the mean ± SEM.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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