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 October 3, 2016; First 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

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 4

Skeletal muscle progenitors with COUP-TFII dysregulation display proliferative defects.

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Skeletal muscle progenitors with COUP-TFII dysregulation display ...
(A) Control and COUP-TFII–expressing myoblasts were cultured for 11 days after virus infection. Data are representative of 3 independent experiments with 3 replicates at each time point. (B and C) BrdU immunostaining and quantification of BrdU incorporation in SC cultures 3 days after COUP-TFII induction. (D) qPCR analyses of the expression of Ccnd1 and Myf5 in COUP-TFII OE myoblasts. Results are representative of 3 independent experiments. (E) Primary SC cultures were subjected to ChIP analyses of COUP-TFII occupancy at the Ccnd1 and Myf5 loci, where the control site, lacking a COUP-TFII–binding motif, served as a negative control. Diagram indicates COUP-TFII–binding sites. Results are representative of 3 independent experiments. (F and G) Diaphragm muscles stained with CCND1 and MYF5 Abs. Scale bars: 50 μm (B), 25 μm (F and G). *P < 0.05 and **P < 0.01 by Student’s t test. Data represent the mean ± SEM.