Dystonin-Deficient Mice Exhibit an Intrinsic Muscle Weakness and an Instability of Skeletal Muscle Cytoarchitecture

• Published in: Developmental biology 1999-06, Vol.210 (2), p.367-380
• Main Authors: Dalpé, Gratien, Mathieu, Martine, Comtois, Alain, Zhu, Ercheng, Wasiak, Sylwia, De Repentigny, Yves, Leclerc, Nicole, Kothary, Rashmi
• Format: Article
• Language: English
• Subjects: actin binding; Actins - metabolism; Animals; Carrier Proteins; Cell Differentiation; Cell Line; Cross-Linking Reagents; Cytoskeletal Proteins - deficiency; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; cytoskeleton; desmin; Desmin - metabolism; Diaphragm - pathology; Diaphragm - physiopathology; Diaphragm - ultrastructure; dystonia musculorum; Dystonin; dystonin/Bpag1; Gene Expression Regulation, Developmental; intermediate filament; Isometric Contraction; linker protein; Mice; Mice, Mutant Strains; mouse; muscle; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscle, Skeletal - ultrastructure; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - pathology; Neurodegenerative Diseases - physiopathology; Recombinant Fusion Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1006/dbio.1999.9263

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.