Disease relevance of Dmd

• These mice show many signs typical of DMD in humans: they show severe progressive muscular dystrophy that results in premature death, they have ultrastructural neuromuscular and myotendinous junction abnormalities, and they aberrantly coexpress myosin heavy chain isoforms within a fiber [1].
• Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy [2].
• The mouse mdx mutation affects muscle and confers a mild dystrophic syndrome, but it is not clear whether this mutation is equivalent to Duchenne/Becker muscular dystrophy in man [3].
• Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fiber leading to the gradual depletion of skeletal muscle [4].
• By analogy with the human X-chromosome, we conclude that the region in the mouse around the G6pd and St14-1 loci may contain two genes corresponding to distinct human myopathies: Emery Dreifuss muscular dystrophy which is known to be closely linked to St14-1 in man and the DMD homologue described here [3].

Psychiatry related information on Dmd

• A significant proportion of DMD affected children suffer also from mental retardation [5].
• Spatial discrimination learning and CA1 hippocampal synaptic plasticity in mdx and mdx3cv mice lacking dystrophin gene products [6].
• Mdx mice, which only lack full-length dystrophin in both muscle and brain, were previously shown to have moderate learning and memory deficits [7].
• Each strain of dystrophin-deficient mice showed a different profile in locomotor activity and deficiencies in the wire maneuver, righting reflex, and negative geotaxis tests [8].
• After this critical period, both spontaneous motility and endurance of mdx mice, although lower than those of controls, do not show statistically significant differences up to 6 months of age [9].

High impact information on Dmd

• Skeletal muscle-specific expression of a utrophin transgene rescues utrophin-dystrophin deficient mice [10].
• Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease usually resulting in death of patients by their early twenties [10].
• Utrophin, a homolog of dystrophin, is confined to the postsynaptic membrane at skeletal neuromuscular junctions and has been implicated in synaptic development [2].
• The discovery of a novel relative of dystrophin substantially broadens the scope for study of this interesting group of proteins and their associated glycoprotein complexes [11].
• It is expressed principally in the brain and spinal cord, and is similar in overall structure to the Dp116 dystrophin isoform [11].

Chemical compound and disease context of Dmd

• Thus, the absence of dystrophin may lead to the loss of a dystrophin-associated glycoprotein, and the reduction in this glycoprotein may be one of the first stages of the molecular pathogenesis of muscular dystrophy [12].
• Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), alpha 2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and alpha 7 integrin congenital muscular dystrophy [13].
• We show that in adult normal and mdx mice (an animal model of Duchenne myopathy) treated with l-arginine, the substrate of nitric oxide synthase (NOS), a pool of utrophin localized at the membrane appeared and increased, respectively [14].
• Hypothyroidism (induced by 8 weeks of oral 0.05% propylthiouracil) heightened the phenotype of mdx mouse dystrophin-deficient myopathy to more closely resemble human Duchenne muscular dystrophy [15].
• An X chromosome-linked mouse mutant (gene symbol, mdx) has been found that has elevated plasma levels of muscle creatine kinase and pyruvate kinase and exhibits histological lesions characteristic of muscular dystrophy [16].

Biological context of Dmd

• Sarcolemmal localization of a truncated utrophin transgene in the dystrophin-deficient mdx mouse significantly improves the dystrophic muscle phenotype [4].
• Dystrophin-deficient mice (mdx) expressing a truncated (trc) utrophin transgene show amelioration of the dystrophic phenotype [17].
• Therefore, up-regulation of utrophin by drug therapy is a plausible therapeutic approach in the treatment of DMD [4].
• Localization of the region homologous to the Duchenne muscular dystrophy locus on the mouse X chromosome [3].
• The molecular structure of dystrophin is very similar to that of the related protein utrophin [4].

Anatomical context of Dmd

• However, the skeletal muscle pathology of the transgenic mdx mice remained severe [18].
• Dp71 was associated with the sarcolemma membrane, where it restored normal expression and localization of all members of the dystrophin-associated glycoprotein complex [18].
• In these mice, Dp71 was localized to the plasma membrane and restored normal levels of dystrophin associated proteins (DAPs), indicating that Dp71 is capable of interacting with the DAPs in a similar manner to dystrophin [19].
• These are two essential functions of muscle fibers, known to be impaired in mdx mouse muscles and Duchenne muscular dystrophy (DMD) patients [17].
• Dystroglycan-dystrophin complexes are believed to have structural and signaling functions by linking extracellular matrix proteins to the cytoskeleton and cortical signaling molecules [20].

Associations of Dmd with chemical compounds

• Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle [12].
• Using the muscle creatine kinase promoter, expression of the alpha 7BX2 integrin chain was increased 2.0-2.3-fold in mdx/utr(-/-) mice [13].
• This suggests that enhanced expression of the alpha 7 beta 1 integrin may provide a novel approach to treat DMD and other muscle diseases that arise due to defects in the dystrophin glycoprotein complex [13].
• Deletions within the cysteine-rich region disrupt the interaction between dystrophin and the DAP complex, leading to a severe dystrophic pathology [21].
• For example, use of the Cn inhibitor cyclosporine A has been shown to delay muscle regeneration following toxin-induced injury and inhibit regeneration in the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy [22].

Physical interactions of Dmd

• Together, these data show that the sarcolemmal localization of nNOS and aquaporin-4 in vivo depends on the presence of a dystrophin-bound alpha-syntrophin PDZ domain [23].
• Caveolin-3 co-immunoprecipitates with antibodies directed against dystrophin, suggesting that they are physically associated as a discrete complex [24].
• Consistent with this induction, we also observed that members of the dystrophin-associated protein (DAP) complex were present at the sarcolemma of mdx/CnA* mouse muscle [25].
• These data suggest that FGF may be a useful cell-binding ligand to enhance gene delivery by Ad and other vectors into skeletal muscle for the gene therapy of Duchenne muscular dystrophy and other muscle-related diseases [26].
• The absence of dystrophin complex leads to disorganization of the force-transmitting costameric cytoskeleton and disruption of sarcolemmal membrane integrity in skeletal muscle [27].

Co-localisations of Dmd

• In cardiocytes, utrophin was colocalized along transverse T tubules with dystrophin [28].
• Here, we show by double-immunofluorescence staining that dystrophin is extensively colocalized with GABAA receptor subunit clusters in these brain regions [29].

Regulatory relationships of Dmd

• We have generated transgenic mdx mice which do not have dystrophin but express Dp71 in their muscle [19].
• A- and B-utrophin have different expression patterns and are differentially up-regulated in mdx muscle [30].
• The association of calpain with the plasma membrane was verified by immunoblots of isolated sarcolemmal membrane from adult mdx and control muscle which showed calpain present predominantly in the cytosol along with some membrane association [31].
• Improved success of myoblast transplantation in mdx mice by blocking the myostatin signal [32].
• To investigate whether reduced muscle precursor cell proliferation can account for the effects of hypothyroidism on repair from injury, immunocytochemistry for neural cell adhesion molecule (NCAM) on muscle precursor cells and autoradiography to detect DNA synthesis were performed in control and mdx TA [15].

Other interactions of Dmd

• Dp71 is a non-muscle product of the Duchenne muscular dystrophy gene [19].
• Genetic crosses with the mdx mouse showed that neither transgenic syntrophin could associate with the sarcolemma in the absence of dystrophin [23].
• Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice [33].
• In contrast, mdx mice that also lack MNF die in the first few weeks of life with a severe myopathy [34].
• Heregulin ameliorates the dystrophic phenotype in mdx mice [35].

Analytical, diagnostic and therapeutic context of Dmd

• Detailed study of these mice should provide novel insights into the pathogenesis of DMD and provide an improved model for rapid evaluation of gene therapy strategies [1].
• We used immunofluorescence techniques and confocal imaging to study the organization of the membrane skeleton of skeletal muscle fibers of mdx mice, which lack dystrophin. beta-Spectrin is normally found at the sarcolemma in costameres, a rectilinear array of longitudinal strands and elements overlying Z and M lines [36].
• Indeed, multiple forms of dystrophin protein were observed by western blot analysis, and the functionality of the products was demonstrated by the restoration of expression and localization of a dystrophin-associated protein, alpha-dystroglycan, in differentiated cells [37].
• Indeed, by immunostaining and immunoblotting we found an approximately 2-fold increase in expression, and distinct extrasynaptic localization, of alpha 7B integrin and utrophin, the functional homolog of dystrophin [38].
• Anchored PCR, primer extension and functional analysis of transfected constructs were used to determine the 5' end of the mRNA and characterize the promoter of this major DMD gene product [39].

References