title: Expression of foetal type acetylcholine receptor is restricted to type 1 muscle fibres in human neuromuscular disorders.
abstract: In adult muscle, acetylcholine receptors (AChR) are restricted mainly to the motor endplate where the adult isoform (alphabetadeltaepsilon) is expressed. When skeletal muscle is denervated in animal models, there is atrophy of the muscle and a marked increase in expression of the AChR foetal isoform (alphabetagammadelta) containing a gamma-subunit. Similar changes in AChR expression are thought to occur in human muscle. While the role of denervation in regulating AChR gene expression has been widely studied, it has not been determined whether the transcriptional programmes responsible for defining different fibre types have an impact on the expression of AChR genes. We investigated biopsies from patients with a wide spectrum of neuromuscular diseases for expression of the AChR alpha- and gamma-subunits using RNase protection assays, alpha/gamma-duplex reverse transcriptase polymerase chain reaction, immunohistochemistry for foetal AChR and RNA in situ hybridization. Muscle from all patients with neurogenic disorders and, to a lesser extent, myogenic disorders, exhibited markedly increased transcription of the AChR gamma-subunit but, in contrast to previous animal studies, did not show increased AChR alpha-subunit. Moreover, both immunohistochemistry and RNA in situ hybridization revealed that AChR gamma-subunit hyperexpression occurred exclusively in atrophic type 1 and not in atrophic type 2 muscle fibres, irrespective of the underlying neuromuscular disease. We conclude that up-regulation of the AChR gamma-subunit in human muscle disorders is restricted to type 1 muscle fibres and, therefore, that AChR gamma-subunit expression is controlled by a muscle fibre type-restricted transcriptional programme. The factors influencing expression of this and other functional proteins should be relevant to the understanding and treatment of a range of neuromuscular disorders.
authors.affiliation: Institute of Pathology, University of Würzburg, Germany. stefan.gattenloehner@mail.uni-wuerzburg.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Gattenlöhner
authors.forename: Christiane
authors.initials: C
authors.lastname: Schneider
authors.forename: Claus
authors.initials: C
authors.lastname: Thamer
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Klein
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Roggendorf
authors.forename: Frank
authors.initials: F
authors.lastname: Gohlke
authors.forename: Caroline
authors.initials: C
authors.lastname: Niethammer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Czub
authors.forename: Angela
authors.initials: A
authors.lastname: Vincent
authors.forename: Hans-Konrad
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.forename: Alexander
authors.initials: A
authors.lastname: Marx
mesh_terms: D001284:Atrophy; D005326:Fetal Proteins / Q000096:biosynthesis*; D006801:Humans; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism* / Q000473:pathology; D009468:Neuromuscular Diseases / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D011950:Receptors, Cholinergic / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000502:physiology
chemical_list: D005326:Fetal Proteins; D012333:RNA, Messenger; D011950:Receptors, Cholinergic