Title: The FSHD Atrophic Myotube Phenotype Is Caused by DUX4 Expression
Authors: Vanderplanck C, Ansseau E, Charron S, Stricwant N, Tassin A, Laoudj-Chenivesse D, Wilton SD, Coppée F, Belayew A.
Publication date and journal: 28 Oct 2011 in PLos One
This work was done by the group of Alexandra Belayew in Mons, Belgium, in collaboration with Dalila Laoudj-Chenivesse from Montpellier, France, and Professor Steve D. Wilton from Perth, Australia, who does much work with exon skipping in Duchenne. Muscle cells of healthy individuals cultured in the laboratory in which DUX4 was introduced were much thinner (atrophic) than muscle cells without active DUX4. (Such thin muscle cells are seen in FSHD.) A number of genes characteristic for the diseased muscle were also found to be activated (Atrogin1, MuRF1, CRYM and TP53). These genes may be used to measure the effect of drugs.
Next, the researcher developed siRNA molecules against DUX4 (these are molecules that cause degradation of the DUX4 messenger RNA so no more DUX4 protein is made). Muscle cells cultured in the laboratory with active DUX4 which were treated with this anti-DUX4 siRNA were less thin 8 days after treatment than untreated muscle cells. They made less DUX4 and TP53 proteins. Antisense Oligonucleotides (AOs) were then developed against DUX4. This is a different kind of anti-molecule which is used for exon skipping in Duchenne. Muscle cells from people with FSHD cultured in the laboratory and treated with a low concentration of anti-DUX4 AOs had less DUX4 and TP53, without much effect on DUX4c, a gene similar to DUX4 which probably has an important function in the human body.
The group of Alexandra Belayew and other research groups worldwide are now working on developing DUX4 mouse models to test whether these anti-DUX4 molecules can slow, stop or hopefully even improve the health of diseased animals.
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