Study provides potential therapies for an inherited form of muscular dystrophy

By screening existing compounds and experimental drugs, a team of researchers from Fred Hutchinson Cancer Research Center, Saint Louis University, the University of Rochester Medical Center, and Leiden University Medical Center, have identified novel drug targets for a prevalent form of muscular dystrophy.

Muscular dystrophies are a group of diseases that trigger muscle weakness and loss. Over time, the muscle weakness makes the people unable to carry out daily activities. An inherited form of muscular dystrophy, known as facioscapulohumeral muscular dystrophy (FSHD), is relatively hard to treat. FSHD initially affects the muscles of the face, shoulders, and upper arms, and many of the patients become severely disabled.

The cause of FSHD is a defect in the DUX4 gene. DUX4 normally is silent in adult skeletal muscle. In FSHD, however, DUX4 gets expressed and activates destructive reactions in muscle cells, leading to muscle degeneration. Dr. Francis Sverdrup, a co-senior author of the new study and a researcher at Saint Louis University, noted that inappropriate expression of DUX4 is toxic to muscle cells.

Therefore, suppressing DUX4 is a logical approach to halting the progression of FSHD. But due to a lack of understanding of mechanisms underlying DUX4 expression as well as a lack of drug targets, at present, there is no therapy for FSHD.

In order to identify molecules that could decrease DUX4 expression, Dr. Sverdrup and his team screened libraries of compounds with epigenetic activities and experimental drugs. They tested these molecules in FSHD patient-derived skeletal muscle cell cultures and measured the levels of DUX4 expression in these cells. By doing so, they identified several classes of molecules that inhibit DUX4, including BET inhibitors and agonists of the beta-2 adrenergic receptor.

A BET inhibitor is a molecule that inhibits one or several members of the BET protein family. The BET protein family consists of four members -- BRD2, BRD3, BRD4, and BRDT -- that largely function as transcriptional coactivators. BET proteins are clinically linked to many human diseases, and therefore lots of research institutions and pharmaceutical companies are engaged in the development of potent and selective BET inhibitors as therapeutics.

The beta-2 adrenergic receptor, or called ADRB2, is a member of the G protein coupled receptors. Mutations in ADRB2 have been associated with higher risk for asthma, obesity, and diabetes. Beta adrenergic agonists or Beta agonists have already been used in the treatment of diseases like asthma.

For this work, the team found that BET inhibitors might suppress DUX4 expression by blocking the activity of BRD4, while beta-2 adrenergic receptor agonists might suppress DUX4 expression by increasing cAMP levels.

Collectively, these data not only illuminate unexpected roles of BET proteins and beta-2 adrenergic receptor signaling in regulating DUX4 expression but also offer new therapeutic strategies for FSHD. Dr. Sverdrup and other researchers participating in the study have published their findings in the professional journal Skeletal Muscle.
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