title: Parallel protein and transcript profiles of FSHD patient muscles correlate to the D4Z4 arrangement and reveal a common impairment of slow to fast fibre differentiation and a general deregulation of MyoD-dependent genes.
abstract: Here, we present the first study of a human neuromuscular disorder at transcriptional and proteomic level. Autosomal dominant facio-scapulo-humeral muscular dystrophy (FSHD) is caused by a deletion of an integral number of 3.3-kb KpnI repeats inside the telomeric region D4Z4 at the 4q35 locus. We combined a muscle-specific cDNA microarray platform with a proteomic investigation to analyse muscle biopsies of patients carrying a variable number of KpnI repeats. Unsupervised cluster analysis divides patients into three classes, according to their KpnI repeat number. Expression data reveal a transition from fast-glycolytic to slow-oxidative phenotype in FSHD muscle, which is accompanied by a deficit of proteins involved in response to oxidative stress. Besides, FSHD individuals show a disruption in the MyoD-dependent gene network suggesting a coregulation at transcriptional level during myogenesis. We also discuss the hypothesis that D4Z4 contraction may affect in trans the expression of a set of genes involved in myogenesis, as well as in the regeneration pathway of satellite cells in adult tissue. Muscular wasting could result from the inability of satellite cells to successfully differentiate into mature fibres and from the accumulation of structural damages caused by a reactive oxygen species (ROS) imbalance induced by an increased oxidative metabolism in fibres.
authors.affiliation: CRIBI Biotechnology Centre and Department of Biology, Università degli Studi di Padova, Padova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Celegato
authors.forename: Daniele
authors.initials: D
authors.lastname: Capitanio
authors.forename: Mario
authors.initials: M
authors.lastname: Pescatori
authors.forename: Chiara
authors.initials: C
authors.lastname: Romualdi
authors.forename: Beniamina
authors.initials: B
authors.lastname: Pacchioni
authors.forename: Stefano
authors.initials: S
authors.lastname: Cagnin
authors.forename: Agnese
authors.initials: A
authors.lastname: Viganò
authors.forename: Luca
authors.initials: L
authors.lastname: Colantoni
authors.forename: Shajna
authors.initials: S
authors.lastname: Begum
authors.forename: Enzo
authors.initials: E
authors.lastname: Ricci
authors.forename: Robin
authors.initials: R
authors.lastname: Wait
authors.forename: Gerolamo
authors.initials: G
authors.lastname: Lanfranchi
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gelfi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002648:Child; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D018656:Muscle Fibers, Fast-Twitch / Q000473:pathology*; D018657:Muscle Fibers, Slow-Twitch / Q000473:pathology*; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017570:MyoD Protein / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D011506:Proteins