title: The FSHD atrophic myotube phenotype is caused by DUX4 expression.
abstract: BACKGROUND
  Facioscapulohumeral muscular dystrophy (FSHD) is linked to deletions in 4q35 within the D4Z4 repeat array in which we identified the double homeobox 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.
  
  
  RESULTS
  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
  These results constitute a proof of concept for the development of therapeutic approaches for FSHD targeting DUX4 expression.
authors: Laboratory of Molecular Biology, University of Mons, Mons, Belgium.
authors: Céline
authors: C
authors: Vanderplanck
authors: Eugénie
authors: E
authors: Ansseau
authors: Sébastien
authors: S
authors: Charron
authors: Nadia
authors: N
authors: Stricwant
authors: Alexandra
authors: A
authors: Tassin
authors: Dalila
authors: D
authors: Laoudj-Chenivesse
authors: Steve D
authors: SD
authors: Wilton
authors: Frédérique
authors: F
authors: Coppée
authors: Alexandra
authors: A
authors: Belayew
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009124:Muscle Proteins / Q000378:metabolism; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology*; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000378:metabolism* / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D034622:RNA Interference / Q000187:drug effects; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D014162:Transfection; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D015415:Biomarkers; C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D009124:Muscle Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000070584:Tripartite Motif Proteins; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases