Disease relevance of Dmd

• Here we present evidence for a 4.8kb transcript from the DMD locus which is ubiquitously expressed but is particularly abundant in Schwannoma cells where dystrophin could not be detected [1].
• Dystrophin was distributed exclusively in the membrane of myocytes in the normally perfused heart but was redistributed to the myofibril fraction after 30 min of ischemia and was lost from both of these compartments during reperfusion in the presence or absence of BDM [2].
• The loss of dystrophin preceded uptake of the membrane-impermeable Evans blue dye by myocytes that occurred after the withdrawal of BDM and was associated with creatine kinase release and the development of contracture [2].
• The abnormal retinal neurotransmission observed in Duchenne muscular dystrophy patients has been attributed to altered expression of C-terminal products of the dystrophin gene in this tissue [3].
• Genetic strategies to replace defective dystrophin with utrophin in individuals with muscular dystrophy requires full characterization of these proteins [4].

High impact information on Dmd

• Immunofluorescence in rat skeletal muscle colocalizes GLUT4 with dystrophin, both intrinsic to muscle fibers [5].
• We have identified isoforms of dystrophin and utrophin, a dystrophin homologue, expressed in astrocytes and examined their expression patterns during dibutyryl-cAMP (dBcAMP)-induced morphological differentiation of astrocytes [6].
• These findings suggest that most of the dystrophin/utrophin-dystroglycan complex on cell membrane in cultured astrocytes was replaced by the Dp71-dystroglycan complex during morphological differentiation [6].
• Differential expression of dystrophin isoforms and utrophin during dibutyryl-cAMP-induced morphological differentiation of rat brain astrocytes [6].
• The results support the conclusions that dystrophin and beta-dystroglycan directly interact at the cytoplasmic face of the rat cardiac muscle plasma membrane [7].

Chemical compound and disease context of Dmd

• The expression of dystrophin in a placebo group and in a group that received 5 mg prednisone/kg body weight per day with and without performing exercise was studied with Western blotting [8].
• We have recently demonstrated that a significant cardiac damage including myocytes injury, inflammation, and fibrosis, was found in dystrophin-deficient myocardium during pressure overload [Kamogawa et al., 2001: Cardiovasc Res 50:509-515] [9].

Biological context of Dmd

• Dystrophin (Xp21), a new phenotype marker of cultured rat aortic myocytes [10].
• Sequencing of the 5' end of a clone isolated from a rat Schwannoma cDNA library, shows that the 4.8kb transcript shares exons with the carboxy terminal end of dystrophin but the 5' untranslated region is not contained within the dystrophin transcript [1].
• Early responses to NGF-induced neuronal differentiation, such as the cessation of cell division and the activation of ERK1/2 proteins, were normal in the antisense-Dp71 cells [11].
• To determine the role of Dp71 in neuronal cells, we generated PC12 cell lines in which Dp71 protein levels were controlled by stable transfection with either antisense or sense constructs [11].
• PURPOSE: The abnormal retinal electrophysiology observed in patients with Duchenne muscular dystrophy (DMD) has been attributed to an altered expression of C-terminal products of the dystrophin gene [12].

Anatomical context of Dmd

• Dystrophin is a low-abundance cytoskeletal protein involved in the maintenance of membrane integrity in striated muscle [10].
• Dystrophin was demonstrated to be a true phenotype marker of cultured rat aortic smooth muscle cells, particularly with respect to their actual contractility [10].
• Immunocytochemistry studies confirm the expression of this protein in nerve cells, a tissue in which full length dystrophin is not detected [1].
• The muscle-specific promoter of the dystrophin gene is active in skeletal, cardiac, and smooth muscles and is specifically stimulated during differentiation of myoblasts into multinucleated myotubes [13].
• Dystrophin Dp71 is required for neurite outgrowth in PC12 cells [11].

Associations of Dmd with chemical compounds

• Antisense-Dp71 cells exhibited a marked suppression of neurite outgrowth upon the induction with NGF or dibutyryl cyclic AMP [11].
• We find strong immunoreactivity against the alpha 7B integrin subunit and dystrophin, and slight reactivity against the alpha 7A integrin at all intrafascicular fibre terminations (IFTs), as well as at the muscle-tendon junction (MTJ) [14].
• Subcellular localization of components of the dystrophin glycoprotein complex in cultured retinal muller glial cells [15].
• Upon withdrawal of BDM, however, EB accumulated in dystrophin-depleted cardiomyocytes [16].
• Reperfusion with the contractile blocker 2,3-butanedione monoxime (BDM) resulted in no accumulation of EB in cardiomyocytes despite the loss of dystrophin [16].

Physical interactions of Dmd

• The dystrophin-glycoprotein complex, which comprises alpha- and beta-dystroglycan, sarcoglycans, and utrophin/dystrophin, links the cytoskeleton to agrin and laminin in the basal lamina in muscle and epithelial cells [17].
• Thus, the present results also support the hypothesis that dystrophin interacts with dystroglycan in cerebellar Purkinje neurons [18].

Other interactions of Dmd

• Utrophin (a dystrophin-related protein) is an ubiquitous protein whose role is still unclear [10].
• The extensive contact made by dystrophin on actin may be used in vivo to help muscles dissipate mechanical stress from the contractile apparatus to the extracellular matrix [4].
• Dystrophin, dystrophin-related protein (DRP, utrophin) and dystroglycan are present not only in muscles but also in the brain [18].
• Dystrobrevin is a newly discovered dystrophin-associated protein that is classified as alpha- and beta-dystrobrevin [19].
• Denervated muscle displayed distinct downregulation of nNOS with preserved expression of dystrophin [20].

Analytical, diagnostic and therapeutic context of Dmd

• Ischemic preconditioning-mediated restoration of membrane dystrophin during reperfusion correlates with protection against contraction-induced myocardial injury [2].
• In the Western blot analysis, alpha-dystrobrevin and dystrophin were first detected as visible bands on days 5 and 7, respectively [21].
• Loss of intracellular dystrophin: a potential mechanism for myocardial reperfusion injury [16].
• Furthermore, quantification of immunofluorescence in labeled transverse sections reveals that beta-spectrin is also concentrated in perijunctional regions, in parallel with an increase in labeling of VGSCs and ankyrinG, but not of dystrophin [22].
• Here, electron microscopy and 3D reconstruction of F-actin decorated with utrophin and dystrophin actin-binding constructs were performed using Utr261 (utrophin's CH domain pair), Utr416 (utrophin's CH domains and first spectrin-repeat) and Dys246 (dystrophin's CH domain pair) [4].

References