Decreased Myocardial nNOS, Increased iNOS and Abnormal ECGs in Mouse Models of Duchenne Muscular Dystrophy

Bia, Britta; Cassidy, P J; Young, Martin E.; Rafael, Jill A.; Leighton, Brendan; Davies, Kay E.; Radda, George K.; Clarke, Kieran

doi:10.1006/jmcc.1999.1018

Cited by 138 publications

(126 citation statements)

References 16 publications

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“…35 It is not likely to be the result of cardiac axis deviation, as it can be detected to a similar degree in any of the limb leads (Supplementary Figure 3). Therefore, changes in the S/R ratio might be due to epimyocardial distribution of cardiac fibrosis, which is evident in untransduced mdx mice in this study as well as in autopsy cases of DMD patients.…”

Section: Discussionmentioning

confidence: 97%

“…Reduction of the S/R ratio is another indication of intraventricular conduction abnormalities in mdx mice. 35 It initially appeared at B8 Figure 8 Voluntary wheel running. A computerized wheel system was utilized to estimate daily running distance (a) and cumulative running distance (b).…”

Section: Discussionmentioning

confidence: 99%

“…Mice subjected to autonomic blockade were excluded from ECG recordings for the following 48 h. The S/R ratio represents the ratio of the amplitude of S waves to R waves on lead II. 35 Immunofluorescence staining of dystrophin/microdystrophin Slide mounted sections measuring 8 mm thick from the heart, diaphragm and quadriceps were stained according to the following procedure. First, the blocking solution from the Mouse-on-Mouse kit (Vector Laboratories, Burlingame, CA, USA) was applied for 1 h at room temperature.…”

Section: Electrocardiogrammentioning

confidence: 99%

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Improvement of cardiac fibrosis in dystrophic mice by rAAV9-mediated microdystrophin transduction

et al. 2011

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Duchenne muscular dystrophy (DMD) is the most common form of the progressive muscular dystrophies characterized by defects of the dystrophin gene. Although primarily characterized by degeneration of the limb muscles, cardiomyopathy is a major cause of death. Therefore, the development of curative modalities such as gene therapy is imperative. We evaluated the cardiomyopathic features of mdx mice to observe improvements in response to intravenous administration of recombinant adeno-associated virus (AAV) type 9 encoding microdystrophin. The myocardium was extensively transduced with microdystrophin to significantly prevent the development of fibrosis, and expression persisted for the duration of the study. Intraventricular conduction patterns, such as the QRS complex duration and S/R ratio in electrocardiography, were also corrected, indicating that the transduced microdystrophin has a protective effect on the dystrophin-deficient myocardium. Furthermore, BNP and ANP levels were reduced to normal, suggesting the absence of cardiac dysfunction. In aged mice, prevention of ectopic beats as well as echocardiographic amelioration was also demonstrated with improved exercise performance. These findings indicate that AAV-mediated cardiac transduction with microdystrophin might be a promising therapeutic strategy for the treatment of dystrophin-deficient cardiomyopathy.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Electrocardiogrammentioning

confidence: 99%

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Improvement of cardiac fibrosis in dystrophic mice by rAAV9-mediated microdystrophin transduction

et al. 2011

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“…Two reports have suggested that dystrophin-deficient hearts (32) and cardiomyocytes (33) exhibit impaired nNOS activity. Despite this apparent similarity of the effect of dystrophin deficiency on cardiac and skeletal muscle NOS signaling, another recent study has demonstrated that in contrast to skeletal muscle, nNOS is not physically associated with the DGC in cardiac muscle (34).…”

Section: Significancementioning

confidence: 99%

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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“…In dystrophin-deficient skeletal muscle, neuronal NO synthase (nNOS, one of the enzymes responsible for NO production) is displaced away from its normal subsarcolemmal location to the cytoplasm, where its mislocalization and decreased activity level are thought to contribute to muscle pathology (10)(11)(12)(13). In the dystrophic heart, a significant down-regulation of nNOS activity has also been reported to occur (14). Conversely, overexpression of an nNOS transgene in the mdx mouse heart was found to mitigate the inflammation, fibrosis, and electrocardiographic abnormalities that develop in older mdx mice (15).…”

mentioning

confidence: 99%

Sildenafil and cardiomyocyte-specific cGMP signaling prevent cardiomyopathic changes associated with dystrophin deficiency

Khairallah

Young

et al. 2008

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

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We recently demonstrated early metabolic alterations in the dystrophin-deficient mdx heart that precede overt cardiomyopathy and may represent an early ''subclinical'' signature of a defective nitric oxide (NO)/cGMP pathway. In this study, we used genetic and pharmacological approaches to test the hypothesis that enhancing cGMP, downstream of NO formation, improves the contractile function, energy metabolism, and sarcolemmal integrity of the mdx heart. We first generated mdx mice overexpressing, in a cardiomyocyte-specific manner, guanylyl cyclase (GC) (mdx/GC ؉/0 ). When perfused ex vivo in the working mode, 12-and 20-week-old hearts maintained their contractile performance, as opposed to the severe deterioration observed in age-matched mdx hearts, which also displayed two to three times more lactate dehydrogenase release than mdx/GC ؉/0 . At the metabolic level, mdx/GC ؉/0 displayed a pattern of substrate selection for energy production that was similar to that of their mdx counterparts, but levels of citric acid cycle intermediates were significantly higher (36 ؎ 8%), suggesting improved mitochondrial function. Finally, the ability of dystrophin-deficient hearts to resist sarcolemmal damage induced in vivo by increasing the cardiac workload acutely with isoproterenol was enhanced by the presence of the transgene and even more so by inhibiting cGMP breakdown using the phosphodiesterase inhibitor sildenafil (44.4 ؎ 1.0% reduction in cardiomyocyte damage). Overall, these findings demonstrate that enhancing cGMP signaling, specifically downstream and independent of NO formation, in the dystrophin-deficient heart improves contractile performance, myocardial metabolic status, and sarcolemmal integrity and thus constitutes a potential clinical avenue for the treatment of the dystrophin-related cardiomyopathies.cardiomyopathy ͉ isotopes ͉ perfusion ͉ energy metabolism ͉ nitric oxide

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Decreased Myocardial nNOS, Increased iNOS and Abnormal ECGs in Mouse Models of Duchenne Muscular Dystrophy

Cited by 138 publications

References 16 publications

Improvement of cardiac fibrosis in dystrophic mice by rAAV9-mediated microdystrophin transduction

Improvement of cardiac fibrosis in dystrophic mice by rAAV9-mediated microdystrophin transduction

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

Sildenafil and cardiomyocyte-specific cGMP signaling prevent cardiomyopathic changes associated with dystrophin deficiency

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