Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

Meyers, Tatyana A.; Townsend, De Wayne

doi:10.3390/ijms20174098

Cited by 95 publications

(123 citation statements)

References 206 publications

(305 reference statements)

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“…Our data show that the stimulated cGMP response is significantly larger on inhibition of PDE2A than PDE5, both in control ( p = 0.048) and in mdx myocytes ( p = 0.0002). Our findings are consistent with the view that lack of therapeutic benefit with sildenafil may result from PDE5 inhibition producing only a modest increase in cGMP [ 3 ] and indicate PDE2A inhibition as an alternative therapeutic intervention, particularly in combination with NO donors/sGC activators [ 40 ].…”

Section: Discussionsupporting

confidence: 90%

“…On the other hand, deranged NO-cGMP signalling within the myocyte can also be directly responsible for cell damage [ 34 ]. To complicate the picture, in dystrophic cardiac myocytes nNOS activity is reduced but eNOS is unchanged and iNOS activity is elevated, making the effects of NO-dependent physiology difficult to predict [ 3 ]. Our findings of a significant deficit of cGMP levels in dystrophic NVM, that is present early on and precede the development of a cardiac phenotype, suggest that alteration of cardiac myocyte cGMP signalling may be an early trigger of the CM associated to DMD.…”

Section: Discussionmentioning

confidence: 99%

“…Our analysis indicates that both in unstimulated cells and upon ISO stimulation the cAMP response at the OMM is attenuated in mdx . This may lead to a limited ability of the mitochondria in dystrophic hearts to synthesise ATP, particularly in conditions of increased cardiac workloads [ 3 ]. Further investigations will be required to establish whether these cAMP-dependent mechanisms contribute to the CM associated with DMD and whether correction of cAMP signals at the mitochondria may be beneficial therapeutically.…”

Section: Discussionmentioning

confidence: 99%

“…The dilated CM that typically associates with DMD results from a complex combination of pathological processes. While it is clear that the pathological alteration involves myocardial wasting and myocardial remodelling [ 3 ], the early molecular events that trigger the cardiac remodelling process remain incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

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Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy

Brescia

Chao

Koschinski

et al. 2020

IJMS

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Duchenne muscular dystrophy (DMD) is the most frequent and severe form of muscular dystrophy. The disease presents with progressive body-wide muscle deterioration and, with recent advances in respiratory care, cardiac involvement is an important cause of morbidity and mortality. DMD is caused by mutations in the dystrophin gene resulting in the absence of dystrophin and, consequently, disturbance of other proteins that form the dystrophin-associated protein complex (DAPC), including neuronal nitric oxide synthase (nNOS). The molecular mechanisms that link the absence of dystrophin with the alteration of cardiac function remain poorly understood but disruption of NO-cGMP signalling, mishandling of calcium and mitochondrial disturbances have been hypothesized to play a role. cGMP and cAMP are second messengers that are key in the regulation of cardiac myocyte function and disruption of cyclic nucleotide signalling leads to cardiomyopathy. cGMP and cAMP signals are compartmentalised and local regulation relies on the activity of phosphodiesterases (PDEs). Here, using genetically encoded FRET reporters targeted to distinct subcellular compartments of neonatal cardiac myocytes from the DMD mouse model mdx, we investigate whether lack of dystrophin disrupts local cyclic nucleotide signalling, thus potentially providing an early trigger for the development of cardiomyopathy. Our data show a significant alteration of both basal and stimulated cyclic nucleotide levels in all compartments investigated, as well as a complex reorganization of local PDE activities.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy

Brescia

Chao

Koschinski

et al. 2020

IJMS

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“…Several of the genes examined in this study are linked with cardiac fibrosis. Cardiac fibrosis is a well-known clinical feature of DMD-associated DCM [39], and PDLIM3 was shown to be involved in cardiac collagen deposition [40].…”

Section: Treatment Consequencesmentioning

confidence: 99%

Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation

Vad

Paludan-Müller

Ahlberg

et al. 2020

JCM

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Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide association studies (GWAS) associated AF with other structural genes. In this study, we investigated whether early-onset AF was associated with loss-of-function variants in DCM-associated genes encoding cytoskeletal proteins. Using targeted sequencing, we examined a cohort of 527 Scandinavian individuals with early-onset AF and a control group of individuals free of AF (n = 383). The patients had onset of AF before 50 years of age, normal echocardiogram, and no other cardiovascular disease at onset of AF. We identified six individuals with rare loss-of-function variants in three different genes (dystrophin (DMD), actin-associated LIM protein (PDLIM3), and fukutin (FKTN)), of which two variants were novel. Loss-of-function variants in cytoskeletal genes were significantly associated with early-onset AF when patients were compared with controls (p = 0.044). Using publicly available GWAS data, we performed genetic correlation analyses between AF and 13 other traits, e.g., showing genetic correlation between AF and non-ischemic cardiomyopathy (p = 0.0003). Our data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy.

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Long‐term human IgG treatment improves heart and muscle function in a mouse model of Duchenne muscular dystrophy

Zschüntzsch

Jouvenal

Zhang

et al. 2020

J cachexia sarcopenia muscle

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Background Duchenne muscular dystrophy (DMD) is a progressive muscle‐wasting disease caused by mutations in the dystrophin gene, which leads to structural instability of the dystrophin–glycoprotein‐complex with subsequent muscle degeneration. In addition, muscle inflammation has been implicated in disease progression and therapeutically addressed with glucocorticosteroids. These have numerous adverse effects. Treatment with human immunoglobulin G (IgG) improved clinical and para‐clinical parameters in the early disease phase in the well‐established mdx mouse model. The aim of the present study was to confirm the efficacy of IgG in a long‐term pre‐clinical study in mdx mice. Methods IgG (2 g/kg body weight) or NaCl solution as control was administered monthly over 18 months by intraperitoneal injection in mdx mice beginning at 3 weeks of age. Several clinical outcome measures including endurance, muscle strength, and echocardiography were assessed. After 18 months, the animals were sacrificed, blood was collected for analysis, and muscle samples were obtained for ex vivo muscle contraction tests, quantitative PCR, and histology. Results IgG significantly improved the daily voluntary running performance (1.9 m more total daily running distance, P < 0.0001) and slowed the decrease in grip strength by 0.1 mN, ( P = 0.018). IgG reduced fatigability of the diaphragm (improved ratio to maximum force by 0.09 ± 0.04, P = 0.044), but specific tetanic force remained unchanged in the ex vivo muscle contraction test. Cardiac function was significantly better after IgG, especially fractional area shortening ( P = 0.012). These results were accompanied by a reduction in cardiac fibrosis and the infiltration of T cells ( P = 0.0002) and macrophages ( P = 0.0027). In addition, treatment with IgG resulted in a significant reduction of the infiltration of T cells ( P ≤ 0.036) in the diaphragm, gastrocnemius, quadriceps, and a similar trend in tibialis anterior and macrophages ( P ≤ 0.045) in gastrocnemius, quadriceps, tibialis anterior, and a similar trend in the diaphragm, as well as a decrease in myopathic changes as reflected by a reduced central nuclear index in the diaphragm, tibialis anterior, and quadriceps ( P ≤ 0.002 in all). Conclusions The present study underscores the importance of an inflammatory contribution to the disease progression of DMD. The data demonstrate the long‐term efficacy of IgG in the mdx mouse. IgG is well tolerated by humans and could preferentially complement gene therapy in DMD. ...

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Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

Cited by 95 publications

References 206 publications

Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy

Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy

Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation

Long‐term human IgG treatment improves heart and muscle function in a mouse model of Duchenne muscular dystrophy

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