Nitric oxide signalling pathway in Duchenne muscular dystrophy mice: up-regulation of <scp>L</scp>-arginine transporters

Ramachandran, Jayalakshmi; Schneider, J; Crassous, Pierre-Antoine; Zheng, Ruifang; Gonzalez, J. Patrick; Xie, Lai-Hua; Beuve, Annie; Fraidenraich, Diego; Peluffo, R. Daniel

doi:10.1042/bj20120787

Cited by 36 publications

(43 citation statements)

References 43 publications

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“…Immunofluorescence labeling revealed that nNOS was localized in the cytoplasm, in a striated pattern, and in the nucleus and was not specifically enriched at the sarcolemma of WT or mdx cardiomyocytes at rest (Fig. S1), in agreement with previous reports (33,34). Moreover, stretch did not lead to membrane recruitment of nNOS or otherwise discernibly alter nNOS localization in either WT or mdx cells (Fig.…”

Section: Stretch-induced Nnos Phosphorylation Is Impaired In Dystrophin-supporting

confidence: 79%

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Garbincius

Michele

2015

Proc. Natl. Acad. Sci. U.S.A.

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Patients deficient in dystrophin, a protein that links the cytoskeleton to the extracellular matrix via the dystrophin-glycoprotein complex (DGC), exhibit muscular dystrophy, cardiomyopathy, and impaired muscle nitric oxide (NO) production. We used live-cell NO imaging and in vitro cyclic stretch of isolated adult mouse cardiomyocytes as a model system to investigate if and how the DGC directly regulates the mechanical activation of muscle NO signaling. Acute activation of NO synthesis by mechanical stretch was impaired in dystrophin-deficient mdx cardiomyocytes, accompanied by loss of stretch-induced neuronal NO synthase (nNOS) S1412 phosphorylation. Intriguingly, stretch induced the acute activation of AMP-activated protein kinase (AMPK) in normal cardiomyocytes but not in mdx cardiomyocytes, and specific inhibition of AMPK was sufficient to attenuate mechanoactivation of NO production. Therefore, we tested whether direct pharmacologic activation of AMPK could bypass defective mechanical signaling to restore nNOS activity in dystrophin-deficient cardiomyocytes. Indeed, activation of AMPK with 5-aminoimidazole-4-carboxamide riboside or salicylate increased nNOS S1412 phosphorylation and was sufficient to enhance NO production in mdx cardiomyocytes. We conclude that the DGC promotes the mechanical activation of cardiac nNOS by acting as a mechanosensor to regulate AMPK activity, and that pharmacologic AMPK activation may be a suitable therapeutic strategy for restoring nNOS activity in dystrophin-deficient hearts and muscle.T he muscular dystrophies are a group of muscle wasting disorders characterized by progressive weakening and degeneration of striated muscle. The most common form is Duchenne muscular dystrophy (DMD), an X-linked disorder caused by genetic disruption of dystrophin (1) that affects 1 in 3,500-5,000 males (2, 3). DMD and several other types of muscular dystrophy result from disruption of the dystrophin-glycoprotein complex (DGC), a structure that spans the sarcolemma and forms a mechanical linkage between the cytoskeleton and the extracellular matrix via the association of dystrophin with subsarcolemmal γ-actin and the binding of α-dystroglycan to laminin (4). The generally accepted role for this complex is to act as a molecular shock absorber and stabilize the plasma membrane during muscle contraction. Disruption of the DGC's linkage between the cytoskeleton and extracellular matrix, such as occurs in DMD (1, 5-7) or with the disruption of α-dystroglycan-laminin binding in glycosylation-deficient muscular dystrophies (8, 9), leads to destabilization of the plasma membrane, rendering skeletal muscle fibers and cardiomyocytes susceptible to stretch-or contraction-induced injury and cell death (10)(11)(12)(13)(14).In addition to this structural role, a signaling function for the DGC has been proposed based on its association with several signaling proteins including Grb2-Sos1 (15), MEK and ERK (16), heterotrimeric G protein subunits (17, 18), archvillin (19), and neuronal nitric oxide synthase (n...

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Section: Stretch-induced Nnos Phosphorylation Is Impaired In Dystrophin-supporting

confidence: 79%

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Garbincius

Michele

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…28,29 Neuronal NOS (nNOS) interacts with dystrophin-associated glycoprotein complex at the sarcolemma in skeletal myocytes, and this association is lost in dystrophin deficiency. 28 However, in cardiomyocytes isolated from the mdx mouse, nNOS does not colocalize with dystrophin 30,31 but instead colocalizes with the ryanodine receptor 2 (RyR2) at the sarcoplasmic reticulum. 32 Endothelial NOS localizes to the Golgi complex and the sarcolemma caveolae.…”

Section: Resultsmentioning

confidence: 99%

Nicorandil, a Nitric Oxide Donor and ATP-Sensitive Potassium Channel Opener, Protects Against Dystrophin-Deficient Cardiomyopathy

Afzal

Reiter

Gastonguay

et al. 2016

J Cardiovasc Pharmacol Ther

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“…Alternatively, Nos may also directly affect transcriptional activation of effector genes (Caceres et al, 2011). Human and mice ventricular myocardial sections show a similar SR-related pattern of nNos (Ramachandran et al, 2013; Xu et al, 1999). Interestingly, the slower heart rate of Nos RNAi flies was reversed in Dys −/− mutant background, so that Dys −/− ; Hand > Nos RNAi flies exhibited a significant decrease in both diastolic and systolic intervals.…”

Section: Discussionmentioning

confidence: 80%

Mechanical and non-mechanical functions of Dystrophin can prevent cardiac abnormalities in Drosophila

Taghli-Lamallem¹,

Jagla²,

Chamberlain³

et al. 2014

Experimental Gerontology

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Dystrophin-deficiency causes cardiomyopathies and shortens the life expectancy of Duchenne and Becker muscular dystrophy patients. Restoring Dystrophin expression in the heart by gene transfer is a promising avenue to explore as a therapy. Truncated Dystrophin gene constructs have been engineered and shown to alleviate dystrophic skeletal muscle disease, but their potential in preventing the development of cardiomyopathy is not fully understood. In the present study, we found that either the mechanical or the signaling functions of Dystrophin were able to reduce the dilated heart phenotype of Dystrophin mutants in a Drosophila model. Our data suggest that Dystrophin retains some function in fly cardiomyocytes in the absence of a predicted mechanical link to the cytoskeleton. Interestingly, cardiac-specific manipulation of nitric oxide synthase expression also modulates cardiac function, which can in part be reversed by loss of Dystrophin function, further implying a signaling role of Dystrophin in the heart. These findings suggest that the signaling functions of Dystrophin protein are able to ameliorate the dilated cardiomyopathy, and thus might help to improve heart muscle function in micro-Dystrophin-based gene therapy approaches.

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Nitric oxide signalling pathway in Duchenne muscular dystrophy mice: up-regulation of L-arginine transporters

Cited by 36 publications

References 43 publications

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Nicorandil, a Nitric Oxide Donor and ATP-Sensitive Potassium Channel Opener, Protects Against Dystrophin-Deficient Cardiomyopathy

Mechanical and non-mechanical functions of Dystrophin can prevent cardiac abnormalities in Drosophila

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