To explore the molecular and cellular effects of transient DUX4 expression in skeletal muscle

Abstract
Facioscapulohumeral muscular dystrophy (FSHD), is one of the most prevalent neuromuscular genetic
disorders, and it is caused by a loss of epigenetic repression of the D4Z4 repeats at chromosome 4 that then
leads to loss of silencing of DUX4. One of the most mysterious aspects of FSHD is the timing and the extent of
the DUX4 expression. Levels of DUX4 in the affected muscles are either extremely low and/or transient as
attempts to date have failed to detect the protein in situ. Evidence of DUX4 expression is indirect, based on
elevated DUX4 target genes in MRI-guided biopsies from FSHD patients. We developed an FSHD mouse model
(iDUX4pA;HSA) that allows conditional expression of DUX4 in muscle fibers, and which upon low level long-term
expression shows hallmarks of FSHD disease pathology. Because it is inducible and reversible, the
iDUX4pA;HSA mouse model provides a unique opportunity for exploring the hypothesis that DUX4 is only
required to prime muscle for later pathology. Our initial experiments indicate that transient DUX4 expression is
sufficient to induce long-term abnormalities in muscle tissue including an increased frequency of FAPs, an
excess of the fibrotic extracellular matrix, and the inability of the muscle to completely recover after injury. The
research proposed in this application aims to explore the long-lasting effect of transient DUX4 expression on
muscle physiology and histology, cellular alterations, and epigenetic state of the genome in the muscle of FSHD
mouse models. They will test the hypothesis that the echo of DUX4 expression, independent of DUX4 expression
itself, can contribute to muscle pathology.

Grant Number: 5R01AR081228-04
NIH Institute/Center: NIH
Principal Investigator: Darko Bosnakovski