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Animal Model for Type of Muscular Dystrophy Offers Platform for Research and Studies on Potential Therapies

According to researchers at the University of Minnesota, they have developed an animal research model for facioscapulohumeral muscular dystrophy (FSHD). The model is intended to be used for muscle regeneration research, as well as studies of the effectiveness of potential therapies for FSHD, a university news release reports.

The research appears in the current edition of the journal Cell Reports.

Michael Kyba, PhD, lead researcher and associate professor in the Medical School at the University of Minnesota, states that there were two reasons researchers felt an animal model would help advance progress towards a cure for FSHD, “First, it would allow us to understand what [the protein] DUX4 does in muscle to cause muscle loss, and second, it would provide a system in which efficacy of potential therapies could be evaluated before they are tested in humans.”

The release notes the mouse model designed by Kyba and his team is built to allow the disease-associated DUX4 protein to be produced when mice are treated with doxycycline. The amount of DUX4 can reportedly be controlled by varying the dose of doxycycline. Researchers say they expected the mice to be normal until they were treated with doxycycline, however even when DUX4 was in the “off” state, the researchers note that the mice exhibited profound disease effects, some linked to FSHD as well as additional effects not seen in FSHD patients.

To address this issue, the team moved the gene to the X chromosome. The release reports that since females have two X chromosomes, only one of which is actively used in each cell, the female mice were healthy enough to enable the DUX4 mice to reproduce even though all of their male progeny with the DUX4 gene expired. Since multiple levels of turning off the DUX4 gene were necessary to allow mice to survive, researchers add, this showed that DUX4 is more toxic than expected.

Kyba explains that perhaps the most important finding during the research was “what we observed when we transplanted skeletal muscle stem cells.”

The release states that the team could isolate muscle stem cells from male mice prior to the mice’s expiration and when they transplanted them into muscle-damaged recipient mice, they found that the stem cells were able to regenerate new muscles. However, when low doses of doxycycline were given to the recipients to turn on DUX4 in the skeletal muscle stem cells, muscle regeneration was severely impaired. The findings indicate that a defect in skeletal muscle degeneration may contribute to muscle loss in FSHD. The finding also offers a quantitative readout of DUX4 activity, researchers say.

Kyba adds that the work, “in which we count new muscle fibers produced by transplanted DUX4-expressing muscle stem cells, will be very useful in testing therapeutics…”

Source: University of Minnesota Academic Health Center