Zebrafish as a model to understand the impact of inactivity and neuromuscular electrical stimulation on neuromuscular plasticity in Duchenne Muscular Dystrophy
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ABSTRACT:
PROVIDER: PRJNA649806 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12356832_1.fastq.gz | Fastqsanger.gz | |||
| SRR12356832_2.fastq.gz | Fastqsanger.gz | |||
| SRR12356833_1.fastq.gz | Fastqsanger.gz | |||
| SRR12356833_2.fastq.gz | Fastqsanger.gz | |||
| SRR12356834_1.fastq.gz | Fastqsanger.gz |
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Project description:Skeletal muscle plasticity is imperative for functional adaptation to changing demands. Although a great deal is known about the structural and functional plasticity of healthy skeletal muscle, far less is known about plasticity in diseased muscle. Here, we created an experimental design to better understand how dystrophin-deficient zebrafish muscle responds to inactivity versus activity. We tested two inactivity paradigms, intermittent versus extended inactivity, and found that extended inactivity, defined as 72 hours in low-dose tricaine, worsens muscle structure and decreases survival. Strikingly, extended inactivity followed by a single session of neuromuscular electrical stimulation (NMES) further worsens muscle structure and obliterates its ability to regenerate. Next, we tested four unique NMES paradigms that varied in their frequency and voltage, and found that each NMES paradigm differentially affected muscle structure, function, and survival. However, one NMES paradigm, which we refer to as endurance NMES, improved all three components of muscle health. Accompanying these improvements, we observed increased sarcomere lengths as well as larger surface areas, volumes, and filament indices of muscle nuclei. Additionally, time-lapse imaging reveals less degeneration and improved regeneration of the fast-twitch muscle fibers. RNAseq analysis highlights two potential mechanisms, one in which gene expression levels are returned to wild-type levels as well as remodeling of the extracellular matrix. Collectively, these data provide a new methodology with which to study neuromuscular plasticity in healthy versus diseased muscle. In addition, our data clearly indicate that, at least in the zebrafish model, NMES is beneficial whereas inactivity is deleterious for dystrophic muscle.
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Project description:Large animal models for Duchenne muscular dystrophy (DMD) are indispensible for preclinical evaluation of novel diagnostic procedures and treatment strategies. To evaluate functional consequences of Duchenne muscular dystrophy (DMD) in skeletal muscle and myocardium, we used a new genetically engineered dystrophin KO pig model displaying hallmarks of human DMD. Heart and skeletal muscle tissue samples of DMD pigs and wild-type (WT) controls at three different ages were analyzed by label-free proteomics.
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Project description:The focus of this review is on Duchenne muscular dystrophy (DMD), which is caused by the absence of the protein dystrophin and is characterized as a neuromuscular disease in which muscle weakness, increased susceptibility to muscle injury, and inadequate repair appear to underlie the pathology. Considerable attention has been dedicated to studying muscle fiber damage, but data show that both human patients and animal models for DMD present with fragmented neuromuscular junction (NMJ) morphology. In addition to pre- and post-synaptic abnormalities, studies indicate increased susceptibility of the NMJ to contraction-induced injury, with corresponding functional changes in neuromuscular transmission and nerve-evoked electromyographic activity. Such findings suggest that alterations in the NMJ of dystrophic muscle may play a role in muscle weakness via impairment of neuromuscular transmission. Further work is needed to fully understand the role of the NMJ in the weakness, susceptibility to injury, and progressive wasting associated with DMD.
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Project description:Skeletal muscle wasting results from numerous pathological conditions impacting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined. Here, using zebrafish loss of function models combined with in vivo cell biology and proteomic approaches, we identified the endoplasmic reticulum chaperone, BiP, as a novel target of the E3 ubiquitin ligase atrogin-1. A loss in atrogin-1 results in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fibre integrity. We further implicate a disruption in atrogin-1 mediated BiP regulation in the pathogenesis of Duchenne Muscular Dystrophy. We reveal that BiP is not only upregulated in Duchenne Muscular Dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorates pathology in a zebrafish model of Duchenne Muscular Dystrophy. Collectively, our data implicates a novel disease axis in the pathogenesis of Duchenne Muscular Dystrophy, and highlights atrogin-1’s essential role in maintaining muscle homeostasis.
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Project description:gene expression data is from RNA extracted from muscle biopsy samples taken from boys with Duchenne muscular dystrophy (DMD) or pathologically normal controls (CTRL). Each muscle biospy was examined in detail histologically by Dr. Eric P. Hoffman at Children's National Medical Center to determine stage of disease. In addition, the absence or presence of dystrophin was determined via western blot analyses. We utilized Human U133 2.0 arrays to examine the transcriptome of each muscle, and then we compared differential gene expression between DMD patient muscles and CTRL muscules. We set the FDR p value for significance at 0.05 and at least a 1.5 fold difference in DMD/CTRL compared differential gene exrpression between DMD versus Control
2016-07-01 | E-GEOD-38417 | biostudies-arrayexpress
Project description:Duchenne muscular dystrophy is an X-linked monogenic disease caused by mutations in the dystrophin gene (DMD) and characterized by progressive muscle weakness leading to loss of ambulation and significantly decreased life expectancy. Since the current standard of care for Duchenne muscular dystrophy is to merely treat symptoms, there is a dire need for novel treatment modalities that can correct the underlying genetic mutations. While several gene replacement therapies are being explored in clinical trials, one emerging approach that can directly correct mutations in genomic DNA is base editing. We have recently developed CRISPR-SKIP, a base editing strategy to induce permanent exon skipping by introducing C>T or A>G mutations at splice acceptors in genomic DNA, which can be utilized therapeutically to recover dystrophin expression when a genomic deletion leads to an out-of-frame DMD transcript. We now demonstrate that CRISPR-SKIP can be adapted to correct some forms of Duchenne muscular dystrophy by disrupting the splice acceptor in human DMD exon 45 with high efficiency, which enables open reading frame recovery and restoration of dystrophin expression. We also demonstrate that AAV-delivered split-intein base editors edit the splice acceptor of DMD exon 45 in cultured human cells and in vivo, highlighting the therapeutic potential of this strategy.
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Project description:We developed a novel somite-based step-wise strategy for the efficient derivation of functional human myocytes, suggesting that past failures were due to incomplete specification. Treatment with two small molecules inhibiting glycogen synthase kinase 3β (GSK-3β) and the Notch signaling pathway in undifferentiated hPSCs results in the formation of somite-like cells by Day 4 and, subsequently contractile myotubes in vitro around Day 25 with the ability to engraft and actively participate in muscle repair in vivo. Antibody-based purification can enrich homogenous myocyte populations exhibiting genuine myogenic molecular and cellular characteristics, including extraocular muscle-like features. Furthermore, hPSCs derived from patients with multiple neuromuscular diseases successfully give rise to patient-specific skeletal muscle cells bearing signature phenotypes. Human embryonic stem cell were differentiated to skeletal muscle and compared to non-differentiated cells in triplicate biological replicates. For the confirmation of differentiated cell's characteristics and the global mRNA profiles, We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. Further more, we used microarrys for the comparing control and disease gene expression profiles, again in triplicate.
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