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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