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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 6

Protection from dystrophic muscle disease in COUP-TFII–KO mdx mice.

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Protection from dystrophic muscle disease in COUP-TFII–KO
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(A and B) H&E- and von Kossa–stained 4-month-old diaphragm muscles. Images are representative of 4 different animals for each genotype. (C) Hydroxyproline content (μg hydroxyproline/mg muscle) in diaphragm muscles in mdx (n = 9) and COUP-TFII–KO mdx (n = 6) mice at 5 to 6 months of age. (D and E) PAX7 staining of the diaphragm muscle and the number of PAX7+ nuclei per 100 nuclei in mdx (n = 7) and COUP-TFII–KO mdx (n = 6) mice at 4 months of age. (F) Quantification of serum CK levels in mdx (n = 14) and COUP-TFII–KO mdx (n = 12) mice. (G) Ten-month-old mdx (n = 14) and COUP-TFII–KO mdx (n = 15) animals were subjected to treadmill running tests. (H) Grip test in mdx (n = 10) and COUP-TFII KO mdx (n = 12) mice. Ten-month-old male mice were used for each genotype cohort. Scale bars: 100 μm (A and B), 25 μm (D). *P < 0.05 and **P < 0.01, by Student’s t test. Data represent the mean ± SEM.
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