Nitric Oxide and l-Arginine Cause an Accumulation of Utrophin at the Sarcolemma: A Possible Compensation for Dystrophin Loss in Duchenne Muscular Dystrophy

Chaubourt, Emmanuel; Fossier, Philippe; Baux, Gérard; Leprince, C.; Israël, Maurice; Porte, Sabine de la

doi:10.1006/nbdi.1999.0256

Cited by 59 publications

(38 citation statements)

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“…100 The injection of l-arginine or nitric oxide also allowed utrophin upregulation in mdx mice. 101 Recently, the intraperitoneal injection of a TAT-utrophin protein in mdx mice increased their muscle strength. 102 A drug developed by Summit PLC (C110/BM195) to upregulate the utrophin expression was carried out by BioMarin pharmaceuticals in a phase I clinical trial with normal individuals.…”

Section: Other Approachesmentioning

confidence: 99%

Current Status of Pharmaceutical and Genetic Therapeutic Approaches to Treat DMD

Pichavant¹,

et al. 2011

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Duchenne muscular dystrophy (DMD) is a genetic disease affecting about one in every 3,500 boys. This X-linked pathology is due to the absence of dystrophin in muscle fibers. This lack of dystrophin leads to the progressive muscle degeneration that is often responsible for the death of the DMD patients during the third decade of their life. There are currently no curative treatments for this disease but different therapeutic approaches are being studied. Gene therapy consists of introducing a transgene coding for full-length or a truncated version of dystrophin complementary DNA (cDNA) in muscles, whereas pharmaceutical therapy includes the use of chemical/biochemical substances to restore dystrophin expression or alleviate the DMD phenotype. Over the past years, many potential drugs were explored. This led to several clinical trials for gentamicin and ataluren (PTC124) allowing stop codon read-through. An alternative approach is to induce the expression of an internally deleted, partially functional dystrophin protein through exon skipping. The vectors and the methods used in gene therapy have been continually improving in order to obtain greater encapsidation capacity and better transduction efficiency. The most promising experimental approaches using pharmaceutical and gene therapies are reviewed in this article.

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Section: Other Approachesmentioning

confidence: 99%

Current Status of Pharmaceutical and Genetic Therapeutic Approaches to Treat DMD

Pichavant¹,

et al. 2011

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“…NOS transgene expression significantly reduced the concentration of macrophages and ameliorated muscle damage, which indicated the possible benefits of an NO-based anti-inflammatory therapy for DMD (48). Another treatment strategy has used systemic administration of L-arginine, the substrate of nNOS, which was reported to reduce damage of mdx muscle by increasing expression of utrophin (114,115). However, this finding differs from another report that expression of a nNOS transgene in mdx muscle reduced utrophin concentration in muscle fibers (116).…”

Section: Tnf-␣ Tumor Necrosis Factor-␣ (Tnf-␣) Is a Cytokine That Ismentioning

confidence: 99%

Evolving Therapeutic Strategies for Duchenne Muscular Dystrophy: Targeting Downstream Events

Tidball¹,

Wehling‐Henricks

2004

Pediatr Res

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“…Recently, the 5Ј-untranslated region of utrophin-A promoter has been shown to be important for regulation of utrophin protein levels during regeneration as well (Miura et al, 2005). Indeed, several of these molecules or mechanisms are currently being investigated for development of utrophin up-regulation-based therapeutics for DMD (Chaubourt et al, 1999;Krag et al, 2004;St-Pierre et al, 2004;Segalat et al, 2005). However, equally important mechanisms controlling concurrent extrasynaptic down-regulation or repression of utrophin-A in myofibers that must occur to achieve expression at the NMJ rather than generalized expression throughout the sarcolemma remain unaddressed.…”

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confidence: 99%

Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle

Perkins

Basu

Budak

et al. 2007

MBoC

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Utrophin is the autosomal homologue of dystrophin, the protein product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin expression is temporally and spatially regulated being developmentally down-regulated perinatally and enriched at neuromuscular junctions (NMJs) in adult muscle. Synaptic localization of utrophin occurs in part by heregulin-mediated extracellular signal-regulated kinase (ERK)-phosphorylation, leading to binding of GABP␣/␤ to the N-box/EBS and activation of the major utrophin promoter-A expressed in myofibers. However, molecular mechanisms contributing to concurrent extrasynaptic silencing that must occur to achieve NMJ localization are unknown. We demonstrate that the Ets-2 repressor factor (ERF) represses extrasynaptic utrophin-A in muscle. Gel shift and chromatin immunoprecipitation studies demonstrated physical association of ERF with the utrophin-A promoter N-box/EBS site. ERF overexpression repressed utrophin-A promoter activity; conversely, small interfering RNA-mediated ERF knockdown enhanced promoter activity as well as endogenous utrophin mRNA levels in cultured muscle cells in vitro. Laser-capture microscopy of tibialis anterior NMJ and extrasynaptic transcriptomes and gene transfer studies provide spatial and direct evidence, respectively, for ERF-mediated utrophin repression in vivo. Together, these studies suggest "repressing repressors" as a potential strategy for achieving utrophin up-regulation in DMD, and they provide a model for utrophin-A regulation in muscle. INTRODUCTIONDuchenne's muscular dystrophy (DMD) is a fatal neuromuscular disease caused by gene mutations leading to qualitative or quantitative disturbances in dystrophin expression (Hoffman et al., 1987). Dystrophin-related protein or utrophin is considered the autosomal homologue of dystrophin, because it shares extensive sequence homology as well as its size and abundance in muscle (Love et al., 1989;Khurana et al., 1990;Tinsley et al., 1992). Utrophin and dystrophin also share functional properties such as the ability to associate with the dystroglycan complex and bind F-actin (Matsumura et al., 1992;Winder and Kendrick, 1995;Rybakova et al., 2002). Direct evidence for the ability of utrophin to functionally substitute comes from experiments demonstrating that utrophin overexpression driven either by transgenic means Rafael et al., 1998;Tinsley et al., 1998;Fisher et al., 2001) or viral vectors (Gilbert et al., 1999;Wakefield et al., 2000;Cerletti et al., 2003) can rescue dystrophin-deficient muscle. Despite these functional similarities, dystrophin and utrophin exhibit distinct localization in normal adult tissues.Perinatally, utrophin is expressed throughout the sarcolemma, however, its expression declines as that of dystrophin increases (Khurana et al., 1991;Clerk et al., 1993), leading to its spatially restricted expression at neuromuscular and myotendinous junctions (NMJs and MTJs, respectively) of adult myofibers. These features and relevance toward a therapy for DMD provide a powerful impetus for b...

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Nitric Oxide and l-Arginine Cause an Accumulation of Utrophin at the Sarcolemma: A Possible Compensation for Dystrophin Loss in Duchenne Muscular Dystrophy

Cited by 59 publications

References 38 publications

Current Status of Pharmaceutical and Genetic Therapeutic Approaches to Treat DMD

Current Status of Pharmaceutical and Genetic Therapeutic Approaches to Treat DMD

Evolving Therapeutic Strategies for Duchenne Muscular Dystrophy: Targeting Downstream Events

Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle

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