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Background  Facioscapulohumeral muscular dystrophy (FSHD) is linked to deletions in 4q35 within the  D4Z4  repeat array in which we identified the  d o u ble homeobo x  4 ( DUX4)  gene. We found stable DUX4 mRNAs only derived from the most distal  D4Z4  unit and unexpectedly extended to the flanking  pLAM  region that provided an intron and a polyadenylation signal.  DUX4  encodes a transcription factor expressed in FSHD but not control primary myoblasts or muscle biopsies. The DUX4 protein initiates a large transcription deregulation cascade leading to muscle atrophy and oxidative stress, which are FSHD key features.    Methodology/Principal Findings  We now show that transfection of myoblasts with a  DUX4  expression vector leads to atrophic myotube formation associated with the induction of E3 ubiquitin ligases (MuRF1 and Atrogin1/MAFbx) typical of muscle atrophy. DUX4 induces expression of downstream targets deregulated in FSHD such as mu-crystallin and TP53. We developed specific siRNAs and antisense oligonucleotides (AOs) targeting the  DUX4  mRNA. Addition of these antisense agents to primary FSHD myoblast cultures suppressed DUX4 protein expression and affected expression of the above-mentioned markers.    Conclusions/Significance  These results constitute a proof of concept for the development of therapeutic approaches for FSHD targeting  DUX4  expression.

The FSHD Atrophic Myotube Phenotype Is Caused by DUX4 Expression