title: Dystonin-deficient mice exhibit an intrinsic muscle weakness and an instability of skeletal muscle cytoarchitecture.
abstract: Dystonia musculorum (dt) was originally described as a hereditary sensory neurodegeneration syndrome of the mouse. The gene defective in dt encodes a cytoskeletal linker protein, dystonin, that is essential for maintaining neuronal cytoskeletal integrity. In addition to the nervous system, dystonin is expressed in a variety of other tissues, including muscle. We now show that dystonin cross-links actin and desmin filaments and that its levels are increased during myogenesis, coinciding with the progressive reorganization of the intermediate filament network. A disorganization of cytoarchitecture in skeletal muscle from dt/dt mice was observed in ultrastructural studies. Myoblasts from dt/dt mice fused to form myotubes in culture; however, terminally differentiated myotubes contained incompletely assembled myofibrils. Another feature observed in dt/dt myotubes in culture and in skeletal muscle in situ was an accumulation and abnormal distribution of mitochondria. The diaphragm muscle from dt/dt mice was weak in isometric contractility measurements in vitro and was susceptible to contraction-induced sarcolemmal damage. Altogether, our data indicate that dystonin is a cross-linker of actin and desmin filaments in muscle and that it is essential for establishing and maintaining proper cytoarchitecture in mature muscle.
authors.affiliation: Centre for Molecular Medicine, Ottawa General Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Dalpé
authors.forename: M
authors.initials: M
authors.lastname: Mathieu
authors.forename: A
authors.initials: A
authors.lastname: Comtois
authors.forename: E
authors.initials: E
authors.lastname: Zhu
authors.forename: S
authors.initials: S
authors.lastname: Wasiak
authors.forename: Y
authors.initials: Y
authors.lastname: De Repentigny
authors.forename: N
authors.initials: N
authors.lastname: Leclerc
authors.forename: R
authors.initials: R
authors.lastname: Kothary
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins; D002454:Cell Differentiation; D002460:Cell Line; D003432:Cross-Linking Reagents; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D003964:Diaphragm / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D000071821:Dystonin; D018507:Gene Expression Regulation, Developmental; D007537:Isometric Contraction; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000199:Actins; D002352:Carrier Proteins; D003432:Cross-Linking Reagents; D003598:Cytoskeletal Proteins; D003893:Desmin; C095667:Dst protein, mouse; D000071821:Dystonin; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins