Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in α-dystroglycanopathies

Mariko Ikeda, Hiroki Kurahashi, Satoru Noguchi, Takayasu Fukudome, Takeshi Okinaga, Toshifumi Tsukahara, Youichi Tajima, Keiichi Ozono, Ichizo Nishino, Ikuya Nonaka, Tatsushi Toda

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Recent studies have revealed an association between post-translational modification of α-dystroglycan (α-DG) and certain congenital muscular dystrophies known as secondary α-dystroglycanopathies (α-DGpathies). Fukuyama-type congenital muscular dystrophy (FCMD) is classified as a secondary α-DGpathy because the responsible gene, fukutin, is a putative glycosyltransferase for α-DG. To investigate the pathophysiology of secondary α-DGpathies, we profiled gene expression in skeletal muscle from FCMD patients. cDNA microarray analysis and quantitative real-time polymerase chain reaction showed that expression of developmentally regulated genes, including myosin heavy chain (MYH) and myogenic transcription factors (MRF4, myogenin and MyoD), in FCMD muscle fibers is inconsistent with dystrophy and active muscle regeneration, instead more of implicating maturational arrest. FCMD skeletal muscle contained mainly immature type 2C fibers positive for immature-type MYH. These characteristics are distinct from Duchenne muscular dystrophy, suggesting that another mechanism in addition to dystrophy accounts for the FCMD skeletal muscle lesion. Immunohistochemical analysis revealed morphologically aberrant neuromuscular junctions (NMJs) lacking MRF4 co-localization. Hypoglycosylated α-DG indicated a lack of aggregation, and acetylcholine receptor (AChR) clustering was compromised in FCMD and the myodystrophy mouse, another model of secondary α-DGpathy. Electron microscopy showed aberrant NMJs and neural terminals, as well as myotubes with maturational defects. Functional analysis of NMJs of α-DGpathy showed decreased miniature endplate potential and higher sensitivities to d-Tubocurarine, suggesting aberrant or collapsed formation of NMJs. Because α-DG aggregation and subsequent clustering of AChR are crucial for NMJ formation, hypoglycosylation of α-DG results in aberrant NMJ formation and delayed muscle terminal maturation in secondary α-DGpathies. Although severe necrotic degeneration or wasting of skeletal muscle fibers is the main cause of congenital muscular dystrophies, maturational delay of muscle fibers also underlies the etiology of secondary α-DGpathies.

Original languageEnglish
Pages (from-to)1279-1289
Number of pages11
JournalHuman molecular genetics
Volume15
Issue number8
DOIs
Publication statusPublished - 01-04-2006

Fingerprint

Walker-Warburg Syndrome
Neuromuscular Junction
Muscles
Muscular Dystrophies
Skeletal Muscle
Myosin Heavy Chains
Skeletal Muscle Fibers
Cholinergic Receptors
Cluster Analysis
Dystroglycans
Myogenin
Tubocurarine
Glycosyltransferases
Duchenne Muscular Dystrophy
Post Translational Protein Processing
Microarray Analysis
Oligonucleotide Array Sequence Analysis
Genes
Real-Time Polymerase Chain Reaction
Regeneration

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Ikeda, Mariko ; Kurahashi, Hiroki ; Noguchi, Satoru ; Fukudome, Takayasu ; Okinaga, Takeshi ; Tsukahara, Toshifumi ; Tajima, Youichi ; Ozono, Keiichi ; Nishino, Ichizo ; Nonaka, Ikuya ; Toda, Tatsushi. / Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in α-dystroglycanopathies. In: Human molecular genetics. 2006 ; Vol. 15, No. 8. pp. 1279-1289.
@article{216f43969ade483f908234b5bd689528,
title = "Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in α-dystroglycanopathies",
abstract = "Recent studies have revealed an association between post-translational modification of α-dystroglycan (α-DG) and certain congenital muscular dystrophies known as secondary α-dystroglycanopathies (α-DGpathies). Fukuyama-type congenital muscular dystrophy (FCMD) is classified as a secondary α-DGpathy because the responsible gene, fukutin, is a putative glycosyltransferase for α-DG. To investigate the pathophysiology of secondary α-DGpathies, we profiled gene expression in skeletal muscle from FCMD patients. cDNA microarray analysis and quantitative real-time polymerase chain reaction showed that expression of developmentally regulated genes, including myosin heavy chain (MYH) and myogenic transcription factors (MRF4, myogenin and MyoD), in FCMD muscle fibers is inconsistent with dystrophy and active muscle regeneration, instead more of implicating maturational arrest. FCMD skeletal muscle contained mainly immature type 2C fibers positive for immature-type MYH. These characteristics are distinct from Duchenne muscular dystrophy, suggesting that another mechanism in addition to dystrophy accounts for the FCMD skeletal muscle lesion. Immunohistochemical analysis revealed morphologically aberrant neuromuscular junctions (NMJs) lacking MRF4 co-localization. Hypoglycosylated α-DG indicated a lack of aggregation, and acetylcholine receptor (AChR) clustering was compromised in FCMD and the myodystrophy mouse, another model of secondary α-DGpathy. Electron microscopy showed aberrant NMJs and neural terminals, as well as myotubes with maturational defects. Functional analysis of NMJs of α-DGpathy showed decreased miniature endplate potential and higher sensitivities to d-Tubocurarine, suggesting aberrant or collapsed formation of NMJs. Because α-DG aggregation and subsequent clustering of AChR are crucial for NMJ formation, hypoglycosylation of α-DG results in aberrant NMJ formation and delayed muscle terminal maturation in secondary α-DGpathies. Although severe necrotic degeneration or wasting of skeletal muscle fibers is the main cause of congenital muscular dystrophies, maturational delay of muscle fibers also underlies the etiology of secondary α-DGpathies.",
author = "Mariko Ikeda and Hiroki Kurahashi and Satoru Noguchi and Takayasu Fukudome and Takeshi Okinaga and Toshifumi Tsukahara and Youichi Tajima and Keiichi Ozono and Ichizo Nishino and Ikuya Nonaka and Tatsushi Toda",
year = "2006",
month = "4",
day = "1",
doi = "10.1093/hmg/ddl045",
language = "English",
volume = "15",
pages = "1279--1289",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "8",

}

Ikeda, M, Kurahashi, H, Noguchi, S, Fukudome, T, Okinaga, T, Tsukahara, T, Tajima, Y, Ozono, K, Nishino, I, Nonaka, I & Toda, T 2006, 'Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in α-dystroglycanopathies', Human molecular genetics, vol. 15, no. 8, pp. 1279-1289. https://doi.org/10.1093/hmg/ddl045

Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in α-dystroglycanopathies. / Ikeda, Mariko; Kurahashi, Hiroki; Noguchi, Satoru; Fukudome, Takayasu; Okinaga, Takeshi; Tsukahara, Toshifumi; Tajima, Youichi; Ozono, Keiichi; Nishino, Ichizo; Nonaka, Ikuya; Toda, Tatsushi.

In: Human molecular genetics, Vol. 15, No. 8, 01.04.2006, p. 1279-1289.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in α-dystroglycanopathies

AU - Ikeda, Mariko

AU - Kurahashi, Hiroki

AU - Noguchi, Satoru

AU - Fukudome, Takayasu

AU - Okinaga, Takeshi

AU - Tsukahara, Toshifumi

AU - Tajima, Youichi

AU - Ozono, Keiichi

AU - Nishino, Ichizo

AU - Nonaka, Ikuya

AU - Toda, Tatsushi

PY - 2006/4/1

Y1 - 2006/4/1

N2 - Recent studies have revealed an association between post-translational modification of α-dystroglycan (α-DG) and certain congenital muscular dystrophies known as secondary α-dystroglycanopathies (α-DGpathies). Fukuyama-type congenital muscular dystrophy (FCMD) is classified as a secondary α-DGpathy because the responsible gene, fukutin, is a putative glycosyltransferase for α-DG. To investigate the pathophysiology of secondary α-DGpathies, we profiled gene expression in skeletal muscle from FCMD patients. cDNA microarray analysis and quantitative real-time polymerase chain reaction showed that expression of developmentally regulated genes, including myosin heavy chain (MYH) and myogenic transcription factors (MRF4, myogenin and MyoD), in FCMD muscle fibers is inconsistent with dystrophy and active muscle regeneration, instead more of implicating maturational arrest. FCMD skeletal muscle contained mainly immature type 2C fibers positive for immature-type MYH. These characteristics are distinct from Duchenne muscular dystrophy, suggesting that another mechanism in addition to dystrophy accounts for the FCMD skeletal muscle lesion. Immunohistochemical analysis revealed morphologically aberrant neuromuscular junctions (NMJs) lacking MRF4 co-localization. Hypoglycosylated α-DG indicated a lack of aggregation, and acetylcholine receptor (AChR) clustering was compromised in FCMD and the myodystrophy mouse, another model of secondary α-DGpathy. Electron microscopy showed aberrant NMJs and neural terminals, as well as myotubes with maturational defects. Functional analysis of NMJs of α-DGpathy showed decreased miniature endplate potential and higher sensitivities to d-Tubocurarine, suggesting aberrant or collapsed formation of NMJs. Because α-DG aggregation and subsequent clustering of AChR are crucial for NMJ formation, hypoglycosylation of α-DG results in aberrant NMJ formation and delayed muscle terminal maturation in secondary α-DGpathies. Although severe necrotic degeneration or wasting of skeletal muscle fibers is the main cause of congenital muscular dystrophies, maturational delay of muscle fibers also underlies the etiology of secondary α-DGpathies.

AB - Recent studies have revealed an association between post-translational modification of α-dystroglycan (α-DG) and certain congenital muscular dystrophies known as secondary α-dystroglycanopathies (α-DGpathies). Fukuyama-type congenital muscular dystrophy (FCMD) is classified as a secondary α-DGpathy because the responsible gene, fukutin, is a putative glycosyltransferase for α-DG. To investigate the pathophysiology of secondary α-DGpathies, we profiled gene expression in skeletal muscle from FCMD patients. cDNA microarray analysis and quantitative real-time polymerase chain reaction showed that expression of developmentally regulated genes, including myosin heavy chain (MYH) and myogenic transcription factors (MRF4, myogenin and MyoD), in FCMD muscle fibers is inconsistent with dystrophy and active muscle regeneration, instead more of implicating maturational arrest. FCMD skeletal muscle contained mainly immature type 2C fibers positive for immature-type MYH. These characteristics are distinct from Duchenne muscular dystrophy, suggesting that another mechanism in addition to dystrophy accounts for the FCMD skeletal muscle lesion. Immunohistochemical analysis revealed morphologically aberrant neuromuscular junctions (NMJs) lacking MRF4 co-localization. Hypoglycosylated α-DG indicated a lack of aggregation, and acetylcholine receptor (AChR) clustering was compromised in FCMD and the myodystrophy mouse, another model of secondary α-DGpathy. Electron microscopy showed aberrant NMJs and neural terminals, as well as myotubes with maturational defects. Functional analysis of NMJs of α-DGpathy showed decreased miniature endplate potential and higher sensitivities to d-Tubocurarine, suggesting aberrant or collapsed formation of NMJs. Because α-DG aggregation and subsequent clustering of AChR are crucial for NMJ formation, hypoglycosylation of α-DG results in aberrant NMJ formation and delayed muscle terminal maturation in secondary α-DGpathies. Although severe necrotic degeneration or wasting of skeletal muscle fibers is the main cause of congenital muscular dystrophies, maturational delay of muscle fibers also underlies the etiology of secondary α-DGpathies.

UR - http://www.scopus.com/inward/record.url?scp=33645806539&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33645806539&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddl045

DO - 10.1093/hmg/ddl045

M3 - Article

C2 - 16531417

AN - SCOPUS:33645806539

VL - 15

SP - 1279

EP - 1289

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 8

ER -