CAPON expression in skeletal muscle is regulated by position, repair, NOS activity, and dystrophy

Ségalat, Laurent; Grisoni, Karine; Archer, Jonathan D.; Vargas, Cinthya; Bertrand, Anne T.; Anderson, Judy E.

doi:10.1016/j.yexcr.2004.09.007

Cited by 46 publications

(45 citation statements)

References 66 publications

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“…7). Utrophin concentration increased by one-third in groups treated with prednisone (P ϭ 0.05), consistent with effects of deflazacort (75). Levels of Pax7, Ki67, MyoD, and ␤-dystroglycan in protein extracts of muscle did not differ among treatment groups (Table 2).…”

Section: Muscle Precursor Cells By In Situ Hybridizationsupporting

confidence: 66%

“…We showed that L-arginine was very effective in increasing the benefit of steroids for treating mdx dystrophy. Combined glucocorticoids and L-arginine spared limb muscle from exercise-induced damage (4), increased myotube formation, and increased expression of CAPON (a NOS anchor protein) and utrophin that relate to cytoskeleton stability (75) in mdx mouse muscle.…”

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confidence: 99%

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Nitric oxide donors improve prednisone effects on muscular dystrophy in the mdx mouse diaphragm

Mizunoya¹,

Upadhaya²,

Burczynski

et al. 2011

American Journal of Physiology-Cell Physiology

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Mizunoya W, Upadhaya R, Burczynski FJ, Wang G, Anderson JE. Nitric oxide donors improve prednisone effects on muscular dystrophy in the mdx mouse diaphragm. Am J Physiol Cell Physiol 300: C1065-C1077, 2011. First published January 26, 2011 doi:10.1152/ajpcell.00482.2010.-In Duchenne muscular dystrophy (DMD), palliative glucocorticoid therapy can produce myopathy or calcification. Since increased nitric oxide synthase activity in dystrophic mice promotes regeneration, the outcome of two nitric oxide (NO) donor drugs, MyoNovin (M) and isosorbide dinitrate (I), on the effectiveness of the anti-inflammatory drug prednisone (P) in alleviating progression of dystrophy was tested. Dystrophic mdx mice were treated (18 days) as controls or with an NO donor Ϯ P. Fiber permeability and DNA synthesis were labeled by Evans blue dye (EBD) and bromodeoxyuridine uptake, respectively. P decreased body weight gain, M increased quadriceps mass, and I increased heart mass. P increased fiber permeability (%EBDϩ fibers) and calcification in diaphragm. Treatment with NO donors ϩ P (MϩP, IϩP) reduced %EBDϩ fibers and calcification vs. P alone. %EBDϩ fibers in MϩP diaphragm did not differ from control. NO donor treatment reduced proliferation and the population of c-metϩ cells and accelerated fiber regeneration. Concurrent with P, NO donor treatment suppressed two important detrimental effects of P in mice, possibly by accelerating regeneration, rebalancing satellite cell quiescence and activation in dystrophy, and/or increasing perfusion. Results suggest that NO donors could improve current therapy for DMD.Duchenne muscular dystrophy; skeletal muscle; satellite cells; glucocorticoid MUSCULAR DYSTROPHIES are lethal genetic muscle diseases, and the most common form, Duchenne muscular dystrophy (DMD), is caused by mutation in the dystrophin gene (37). Absence of dystrophin from the cytoskeleton in DMD fibers leads to disruption of the sarcolemma by mechanical stress or exercise and progressive muscle weakness and wasting (20,27,56,69). Investigations of possible therapeutic interventions using the mdx mouse model of DMD have examined gene therapy by viral delivery of full-length dystrophin (28) or microdystrophin (97), stem (satellite) cell transplantation (40), and read-through (91) or exon-skipping approaches (2, 55, 93) to restore dystrophin expression. As these investigations are ongoing, pharmacological treatment with glucocorticoids remains the current "gold standard" therapy in DMD.Treatment with prednisone promotes a palliative reduction in inflammation and delays disease progression (57, 58) in DMD. In DMD patients and mdx mice, prednisone and deflazacort reduce the secondary inflammation that extends muscle fiber necrosis outside the region of primary damage that is caused by exercise-induced membrane breaks or eccentric contraction (25, 63). In addition, deflazacort also upregulates the calcineurin/nuclear factor of activated T cells (NFAT) pathway activity, which counteracts the muscle-specific activation of JNK1 that damages...

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Section: Muscle Precursor Cells By In Situ Hybridizationsupporting

confidence: 66%

mentioning

confidence: 99%

Nitric oxide donors improve prednisone effects on muscular dystrophy in the mdx mouse diaphragm

Mizunoya¹,

Upadhaya²,

Burczynski

et al. 2011

American Journal of Physiology-Cell Physiology

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“…The DYC-1 protein does not appear to have any particular motif that might help to understand its function. Its closest vertebrate relative is the CAPON protein, a putative adaptor of the neuronal nitric oxide synthase (nNOS), which is expressed in neurons and in muscle satellite cells (Jaffrey et al, 1998;Segalat et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

DYC-1, a Protein Functionally Linked to Dystrophin inCaenorhabditis elegansIs Associated with the Dense Body, Where It Interacts with the Muscle LIM Domain Protein ZYX-1

Lecroisey

Martin

Mariol

et al. 2008

MBoC

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In Caenorhabditis elegans, mutations of the dystrophin homologue, dys-1, produce a peculiar behavioral phenotype (hyperactivity and a tendency to hypercontract). In a sensitized genetic background, dys-1 mutations also lead to muscle necrosis. The dyc-1 gene was previously identified in a genetic screen because its mutation leads to the same phenotype as dys-1, suggesting that the two genes are functionally linked. Here, we report the detailed characterization of the dyc-1 gene. dyc-1 encodes two isoforms, which are expressed in neurons and muscles. Isoform-specific RNAi experiments show that the absence of the muscle isoform, and not that of the neuronal isoform, is responsible for the dyc-1 mutant phenotype. In the sarcomere, the DYC-1 protein is localized at the edges of the dense body, the nematode muscle adhesion structure where actin filaments are anchored and linked to the sarcolemma. In yeast two-hybrid assays, DYC-1 interacts with ZYX-1, the homologue of the vertebrate focal adhesion LIM domain protein zyxin. ZYX-1 localizes at dense bodies and M-lines as well as in the nucleus of C. elegans striated muscles. The DYC-1 protein possesses a highly conserved 19 amino acid sequence, which is involved in the interaction with ZYX-1 and which is sufficient for addressing DYC-1 to the dense body. Altogether our findings indicate that DYC-1 may be involved in dense body function and stability. This, taken together with the functional link between the C. elegans DYC-1 and DYS-1 proteins, furthermore suggests a requirement of dystrophin function at this structure. As the dense body shares functional similarity with both the vertebrate Z-disk and the costamere, we therefore postulate that disruption of muscle cell adhesion structures might be the primary event of muscle degeneration occurring in the absence of dystrophin, in C. elegans as well as vertebrates.

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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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CAPON expression in skeletal muscle is regulated by position, repair, NOS activity, and dystrophy

Cited by 46 publications

References 66 publications

Nitric oxide donors improve prednisone effects on muscular dystrophy in the mdx mouse diaphragm

Nitric oxide donors improve prednisone effects on muscular dystrophy in the mdx mouse diaphragm

DYC-1, a Protein Functionally Linked to Dystrophin inCaenorhabditis elegansIs Associated with the Dense Body, Where It Interacts with the Muscle LIM Domain Protein ZYX-1

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

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