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.

Dystonin/Bpag1—A link to what?

“…In muscle, dystonin was suggested to link actin filaments to desmin filaments [Dalpé et al, 1999]. This would fit well with its suggested roles in neurons and keratinocytes, and help account for intrinsic muscle weakness observed in the mice [Dalpé et al, 1999].…”

“…Also, incomplete and sometimes erroneous descriptions of the Dst gene ( Fig. 1) have lead to conflicting reports regarding the function and nature of dystonin proteins [Yang et al, 1996;Dalpé et al, 1999;Leung et al, 1999].…”

“…The first reports regarding the essential functions of dystonin in the neuromuscular system focussed on the apparent ability of dystonin to link actin filaments to intermediate filaments [Yang et al, 1996;Dalpé et al, 1999;Leung et al, 1999]. In neurons, dystonin was suggested to be important for cross-linking actin filaments to either neurofilaments via neurofilament heavy (NF-H) [Yang et al, 1996] or to peripherin-containing intermediate filaments [Leung et al, 1999].…”

“…Furthermore, they provided additional sequence information that shed more light on the true nature of the dystonin neuronal and muscle isoforms [see Table 1 ;and Leung et al, 2001]. They demonstrated that dystonin brain and muscle transcripts, which have been shown to be large ( 15 kb) [Dalpé et al, 1998[Dalpé et al, , 1999Leonova and Lomax, 2002], contain a region coding for multiple spectrin repeats and a C-terminal microtubule binding domain (MTBD) in their 3 0 halves. To date, the best evidence indicates that it is the loss of function of a dystonin-a protein with either the isoform 1 or 2 (or both) N-termini ( Figs.…”

Functional and Genetic Analysis of Spectraplakins in Drosophila

“…Furthermore, patient studies suggest potential roles in neural development (Giorda et al, 2004;Vincent et al, 2008), human melanoma (Shimbo et al, 2010), and the infection process of Herpes virus (Pasdeloup, McElwee, Beilstein, Labetoulle, & Rixon, 2013). Finally, studies of dystonin mutant mice reveal further defects in glial cells (Bernier, De Repentigny, Mathieu, David, & Kothary, 1998;Saulnier, De Repentigny, Yong, & Kothary, 2002) potentially linking to multiple sclerosis (Laffitte et al, 2005), and neuromuscular junction defects associated with intrinsic muscle weakness (Boyer, Bernstein, & Boudreau-Larivière, 2010;Dalpe et al, 1999;Poliakova et al, 2014).…”