Dystonin-deficient mice exhibit an intrinsic muscle weakness and an instability of skeletal muscle cytoarchitecture

Dystonia musculorum (dt) was originally described as a hereditary sensory n eurodegeneration syndrome of the mouse. The gene defective in dt encodes a cytoskeletal linker protein, dystonin, that is essential for maintaining ne uronal cytoskeletal integrity. In addition to the nervous system, dystonin is expressed in a variety of other tissues, including muscle. We now show t hat dystonin cross-links actin and desmin filaments and that its levels are increased during myogenesis, coinciding with the progressive reorganizatio n of the intermediate filament network. A disorganization of cytoarchitectu re in skeletal muscle from dt/dt mice was observed in ultrastructural studi es. Myoblasts from dt/dt mice fused to form myotubes in culture; however, t erminally differentiated myotubes contained incompletely assembled myofibri ls. Another feature observed in dt/dt myotubes in culture and in skeletal m uscle 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 sarcolemma l damage. Altogether, our data indicate that dystonin is a cross-linker of actin and desmin filaments in muscle and that it is essential for establish ing and maintaining proper cytoarchitecture in mature muscle. (C) 1999 Acad emic Press.