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.