Disease relevance of Utrn

• Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy [1].
• The amelioration of dystrophic phenotype by heregulin-mediated utrophin up-regulation offers a pharmacological therapeutic modality and obviates many of the toxicity and delivery issues associated with viral vector-based gene therapy for DMD [2].
• Dko muscle (tibialis anterior) was injected with a first generation recombinant adenovirus containing a utrophin minigene [3].
• Expression of full-length utrophin prevents muscular dystrophy in mdx mice [4].
• We found reduced fibrosis and increased expression of dystrophin-associated proteins (DAPs) in association with muscle areas expressing the utrophin minigene, indicating that mini-utrophin can functionally compensate for lack of dystrophin in injected muscles [5].

High impact information on Utrn

• Skeletal muscle-specific expression of a utrophin transgene rescues utrophin-dystrophin deficient mice [6].
• Here we show that expression of a truncated utrophin transgene solely within the skeletal muscle of these mutants prevents premature death and the development of any clinical phenotype [6].
• Utrophin, a homolog of dystrophin, is confined to the postsynaptic membrane at skeletal neuromuscular junctions and has been implicated in synaptic development [1].
• Sarcolemmal localization of a truncated utrophin transgene in the dystrophin-deficient mdx mouse significantly improves the dystrophic muscle phenotype [4].
• These data suggest that systemic upregulation of utrophin in DMD patients may lead to the development of an effective treatment for this devastating disorder [7].

Chemical compound and disease context of Utrn

• 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 [8].
• Using in situ hybridization and immunohistochemistry, we show that dispersion and hypertrophy of granule cells in KA-treated wildtype mice are accompanied by a strong and long-lasting expression of utrophin in somata and proximal dendrites [9].
• However, two of the 15 mAbs also recognised rat/mouse utrophin and both of these detected an additional 62 kDa protein on Western blots of rat C6 glioma cells [10].
• Congenital myasthenic syndromes in two kinships with end-plate acetylcholine receptor and utrophin deficiency [11].

Biological context of Utrn

• During mouse embryogenesis G-utrophin is also seen in the developing sensory ganglia [12].
• Utrophin is a chromosome 6-encoded dystrophin-related protein (DRP), sharing functional motifs with dystrophin [2].
• Prevention of the dystrophic phenotype in dystrophin/utrophin-deficient muscle following adenovirus-mediated transfer of a utrophin minigene [3].
• Despite the described sequence homologies between dystrophin and utrophin, the present results indicate that these proteins have different roles in some specific cardiac cell areas [13].
• The molecular structure of dystrophin is very similar to that of the related protein utrophin [4].

Anatomical context of Utrn

• In contrast, transgenic expression of an activated mutant of Cn in skeletal muscle was shown to increase utrophin expression and reduce overall disease pathology in mdx mice [14].
• B-utrophin is expressed in vascular endothelial cells; A-utrophin is expressed at the neuromuscular junction, choroid plexus, pia mater, and renal glomerulus [15].
• Our results highlight the potential participation of the short utrophin isoform and the cleaved form of beta-dystroglycan in mdx Schwann cell membrane architecture [16].
• Moreover, we showed for the first time that the short isoform of utrophin (Up71) was over-expressed in mdx Schwann cells compared with wild-type [16].
• The recombinant utrophin was distributed homogeneously at the surface of the muscle fibers [17].

Associations of Utrn with chemical compounds

• In the present study, we have therefore focused on the effect of agrin on utrophin expression in cultured C2 myotubes [18].
• In response to Torpedo-, muscle-, or nerve-derived agrin, we observed a significant 2-fold increase in utrophin mRNAs [18].
• The transduced fibers were largely impermeable to the tracer dye Evans blue, suggesting that utrophin protects the surface membrane from breakage [19].
• We injected an adenoviral vector expressing a synthetic utrophin into tibialis anterior muscles of newborn dogs affected with CXMD and examined transgene expression by RNA and protein analysis at 10, 30 and 60 days postinjection in cyclosporin-treated and -untreated animals [5].
• We previously found that L-arginine, the substrate for nitric oxide synthase, significantly increased utrophin level in muscle and targeted it to the sarcolemma [20].

Physical interactions of Utrn

• Electrophoretic mobility shift and supershift assays revealed the presence of a nuclear factor of activated T cells (NFAT) binding site in the utrophin A promoter [21].

Co-localisations of Utrn

• Syntrophin expression co-localizes with utrophin in the choroid plexus and caudate putamen [22].
• In cardiocytes, utrophin was colocalized along transverse T tubules with dystrophin [23].

Regulatory relationships of Utrn

• G-utrophin is expressed in brain sites generally different from the regions expressing beta-dystroglycan [12].
• The utrophin promoter A is transcriptionally regulated in part by heregulin-mediated, extracellular signal-related kinase-dependent activation of the GABP(alpha/beta) transcription factor complex [2].
• In addition, we showed that activation of cellular calpains by Ca2+ ionophore treatment reduces utrophin protein levels in muscle cells and that calpain inhibition prevents this Ca2+ -induced reduction in utrophin levels [24].
• Interleukin 6 induces overexpression of the sarcolemmal utrophin in neonatal mdx skeletal muscle [25].
• Furthermore, this increase in transcriptional activity in response to agrin resulted from a greater number of myonuclei expressing the 1.3-kilobase pair utrophin promoter-nlsLacZ construct [18].

Other interactions of Utrn

• In contrast, utrophin is a specific component of intercalated disks together with beta- and gamma-sarcoglycans, while beta-dystroglycan, alpha- and delta-sarcoglycans are not present [13].
• Utrophin is a calpain substrate in muscle cells [24].
• In dystrophin deficient cardiac muscle, utrophin and beta-sarcoglycan were observed in intercalated disks and at the sarcolemma of each cardiocyte [13].
• Intraperitoneal injections of a small peptide encoding the epidermal growth factor-like region of heregulin ectodomain for 3 months in vivo resulted in up-regulation of utrophin, a marked improvement in the mechanical properties of muscle as evidenced by resistance to eccentric contraction mediated damage, and a reduction of muscle pathology [2].
• Claudin-5 localizes to the lateral membranes of cardiomyocytes and is altered in utrophin/dystrophin-deficient cardiomyopathic mice [26].

Analytical, diagnostic and therapeutic context of Utrn

• Therefore, up-regulation of utrophin by drug therapy is a plausible therapeutic approach in the treatment of DMD [4].
• Finally, electrophoretic mobility shift assays and supershift experiments performed with muscle extracts revealed that the N-box of the utrophin promoter binds GABP [27].
• Accordingly, site-directed mutagenesis of a single N-box motif in the utrophin gene promoter abolished the transcriptional response to heregulin [27].
• Northern blot analysis of multiple adult tissues confirmed that only two major sizes of transcripts are produced from each gene: 13 and 5.5 kb from utrophin and 14 and 4.8 kb from dystrophin [28].
• Western blotting experiments also revealed that the increase in utrophin mRNAs was accompanied by an increase in the levels of utrophin [18].

References