Duchenne muscular dystrophy

Duan, Dongsheng; Goemans, Nathalie; Takeda, Shin’ichi; Mercuri, Eugenio; Aartsma‐Rus, Annemieke

doi:10.1038/s41572-021-00248-3

Cited by 718 publications

(738 citation statements)

References 219 publications

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“…Patients with Duchenne muscular dystrophy (DMD) lack sufficient expression of a functional dystrophin protein in all striated muscles, leading to loss of ambulation by 13 years of age, progressive respiratory insufficiency and dilated cardiomyopathy ( 1 ). Currently, cardiac failure is the leading cause of mortality in DMD with available treatment options having only limited efficacy due to their lack of specificity ( 2–4 ).…”

Section: Introductionmentioning

confidence: 99%

Proteomic analysis identifies key differences in the cardiac interactomes of dystrophin and micro-dystrophin

Wang

Marrosu

Brayson

et al. 2021

Human Molecular Genetics

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ΔR4-R23/ΔCT micro-dystrophin (μDys) is a miniaturized version of dystrophin currently evaluated in a Duchenne muscular dystrophy (DMD) gene therapy trial to treat skeletal and cardiac muscle disease. In pre-clinical studies, μDys efficiently rescues cardiac histopathology, but only partially normalizes cardiac function. To gain insights into factors that may impact the cardiac therapeutic efficacy of μDys, we compared by mass spectrometry the composition of purified dystrophin and μDys protein complexes in the mouse heart. We report that compared to dystrophin, μDys has altered associations with α1- and β2-syntrophins, as well as cavins, a group of caveolae-associated signaling proteins. In particular, we found that membrane localization of cavin-1 and cavin-4 in cardiomyocytes requires dystrophin and is profoundly disrupted in the heart of mdx5cv mice, a model of DMD. Following cardiac stress/damage, membrane-associated cavin-4 recruits the signaling molecule ERK to caveolae, which activates key cardio-protective responses. Evaluation of ERK signaling revealed a profound inhibition, below physiological baseline, in the mdx5cv mouse heart. Expression of μDys in mdx5cv mice prevented the development of cardiac histopathology but did not rescue membrane localization of cavins nor did it normalize ERK signaling. Our study provides the first comparative analysis of purified protein complexes assembled in vivo by full-length dystrophin and a therapeutic micro-dystrophin construct. This has revealed disruptions in cavins and ERK signaling that may contribute to DMD cardiomyopathy. This new knowledge is important for ongoing efforts to prevent and treat heart disease in DMD patients.

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Section: Introductionmentioning

confidence: 99%

Proteomic analysis identifies key differences in the cardiac interactomes of dystrophin and micro-dystrophin

Wang

Marrosu

Brayson

et al. 2021

Human Molecular Genetics

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“…Skeletal muscle biopsies from Becker muscular dystrophy (BMD) patients showed decreased miR-486 expression similar to DMD, demonstrating that reduced miR-486 is correlated to pathology related to the loss or decrease of functional dystrophin protein (Figure 1A). To evaluate this in a DMD mouse model, we assessed miR-486 levels in three different muscle groups across five DMD disease-relevant time points (1,3,6,9, and 12-months-old) in both mdx 5cv and wild type mice.…”

Section: Mainmentioning

confidence: 99%

“…Skeletal muscle is a remarkable organ with intrinsic plasticity due to its regenerative and reparative capabilities in response to exercise, traumatic injury, and disease. In Duchenne muscular dystrophy (DMD), the lack of a functional dystrophin protein causes skeletal muscle weakness, dilated cardiomyopathy, respiratory failure, and premature death 1 . Recent progress in the development of DYSTROPHIN gene restoration approaches, such as EXONDYS 51 (Eteplirsen), has been shown to benefit a subset of DMD patients amenable to the skipping of DYSTROPHIN exon 51 which restores the reading frame 2 .…”

Section: Mainmentioning

confidence: 99%

miR-486 is an epigenetic modulator of Duchenne muscular dystrophy pathologies

Samani

et al. 2021

Preprint

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Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle disorder resulting in muscle weakness and cardiomyopathy. MicroRNAs have been shown to play essential roles in muscle development, metabolism, and disease pathologies. We demonstrated that miR-486 expression is reduced in DMD muscles and its expression levels correlate with dystrophic disease severity. MicroRNA-486 knockout mice developed disrupted myofiber architecture, decreased myofiber size, decreased locomotor activity, increased cardiac fibrosis, and metabolic defects that were exacerbated on the dystrophic mdx5cv background. We integrated RNA-sequencing and chimeric eCLIP-sequencing data to identify direct in vivo targets of miR-486 and associated dysregulated gene signatures in skeletal muscle. In comparison to our DMD mouse muscle transcriptomes, we identified several of these miR-486 muscle targets including known modulators of dystrophinopathy disease symptoms. Together, our studies identify miR-486 as a driver of muscle remodeling in DMD, a useful biomarker for dystrophic disease progression, and highlight chimeric eCLIP-sequencing as a useful tool to identify direct in vivo microRNA target transcripts.

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“…DMD is caused by mutations in the dystrophin gene, which leads to the loss of a functional dystrophin protein (Monaco et al, 1986). DMD is characterized by progressive loss of muscle mass and function due to muscle degeneration, necrosis, and fatty fibrosis, resulting in wheelchair dependence (Ervasti and Campbell, 1993;Bushby et al, 2010;Connolly et al, 2013;Aartsma-Rus et al, 2016;Duan et al, 2021). Eventually, patients die of respiratory failure and/or cardiomyopathy (Finsterer, 2006).…”

Section: Introductionmentioning

confidence: 99%

Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

et al. 2021

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Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by the loss of dystrophin. DMD is associated with muscle degeneration, necrosis, inflammation, fatty replacement, and fibrosis, resulting in muscle weakness, respiratory and cardiac failure, and premature death. There is no curative treatment. Investigations on disease-causing mechanisms offer an opportunity to identify new therapeutic targets to treat DMD. An abnormal elevation of the intracellular calcium (Cai2+) concentration in the dystrophin-deficient muscle is a major secondary event, which contributes to disease progression in DMD. Emerging studies have suggested that targeting Ca2+-handling proteins and/or mechanisms could be a promising therapeutic strategy for DMD. Here, we provide an updated overview of the mechanistic roles the sarcolemma, sarcoplasmic/endoplasmic reticulum, and mitochondria play in the abnormal and sustained elevation of Cai2+ levels and their involvement in DMD pathogenesis. We also discuss current approaches aimed at restoring Ca2+ homeostasis as potential therapies for DMD.

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Duchenne muscular dystrophy

Cited by 718 publications

References 219 publications

Proteomic analysis identifies key differences in the cardiac interactomes of dystrophin and micro-dystrophin

Proteomic analysis identifies key differences in the cardiac interactomes of dystrophin and micro-dystrophin

miR-486 is an epigenetic modulator of Duchenne muscular dystrophy pathologies

Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

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