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Proteome analysis of skeletal muscle samples from a porcine model of Duchenne muscular dystrophy

ABSTRACT: Duchenne muscular dystrophy (DMD) is caused by genetic deficiency of dystrophin and characterized by massive structural and functional changes of skeletal muscle tissue, leading to terminal muscle failure. In this project, proteomics data from skeletal muscle of a genetically engineered DMD pig model were investigated in order to confirm muscular fibrosis and MSOT signals.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Sus Scrofa Domesticus (domestic Pig)

TISSUE(S): Skeletal Muscle

DISEASE(S): Duchenne Muscular Dystrophy

SUBMITTER: Florian Flenkenthaler

LAB HEAD: Dr. Thomas Fröhlich

PROVIDER: PXD016003 | Pride | 2020-01-09

REPOSITORIES: Pride

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Detection of collagens by multispectral optoacoustic tomography as an imaging biomarker for Duchenne muscular dystrophy.

Regensburger Adrian P AP Fonteyne Lina M LM Jüngert Jörg J Wagner Alexandra L AL Gerhalter Teresa T Nagel Armin M AM Heiss Rafael R Flenkenthaler Florian F Qurashi Matthias M Neurath Markus F MF Klymiuk Nikolai N Kemter Elisabeth E Fröhlich Thomas T Uder Michael M Woelfle Joachim J Rascher Wolfgang W Trollmann Regina R Wolf Eckhard E Waldner Maximilian J MJ Knieling Ferdinand F

Nature medicine 20191202 12

Biomarkers for monitoring of disease progression and response to therapy are lacking for muscle diseases such as Duchenne muscular dystrophy. Noninvasive in vivo molecular imaging with multispectral optoacoustic tomography (MSOT) uses pulsed laser light to induce acoustic pressure waves, enabling the visualization of endogenous chromophores. Here we describe an application of MSOT, in which illumination in the near- and extended near-infrared ranges from 680-1,100 nm enables the visualization an ...[more]

PMID: 31792454

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Proteome analysis of skeletal muscle samples from a porcine model of Duchenne muscular dystrophy treated by somatic gene editing

Project description:Duchenne muscular dystrophy (DMD) is caused by genetic deficiency of dystrophin and characterized by massive structural and functional changes of skeletal muscle tissue, leading to terminal muscle failure. In this project, proteomics data from skeletal muscle of a genetically engineered DMD pig model treated by somatic gene editing are shown.

2020-02-05 | PXD014893 | Pride

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The microRNA, miR-133b, functions to slow Duchenne muscular dystrophy pathogenesis

Project description:Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle degeneration. No treatments are currently available to prevent the disease. While the muscle enriched microRNA, miR-133b, has been implicated in muscle biogenesis, its role in DMD remains unknown. To assess miR-133b function in DMD-affected skeletal muscles, we genetically ablated miR-133b in the mdx mouse model of DMD. In the absence of miR-133b, the tibialis anterior muscle of juvenile and adult mdx mice is populated by small muscle fibers and exhibits increased fibrosis, characterized by thickened interstitial space. Additional analysis revealed that loss of miR-133b exacerbates DMD-pathogenesis partly by altering satellite cell numbers and through widespread transcriptomic changes. These include known miR-133b targets as well as genes involved in cell proliferation and fibrosis. Altogether, our data demonstrate that skeletal muscles utilize miR-133b to mitigate the deleterious effects of DMD.

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Project description:Duchenne muscular dystrophy (DMD) causes severe disability of children and death of young men, with an incidence of approximately 1/5,000 male births. Symptoms appear in early childhood, with a diagnosis made around 4, a time where the amount of muscle damage is already significant, preventing early therapeutic interventions that could be more efficient at halting disease progression. In the meantime, the precise moment at which disease phenotypes arise – even asymptomatically – is still unknown. Thus, there is a critical need to better define DMD onset as well as its first manifestations, which could help identify early disease biomarkers and novel therapeutic targets. In this study, we have used human induced pluripotent stem cells (hiPSCs) from DMD patients to model skeletal myogenesis, and compared their differentiation dynamics to healthy control cells by a comprehensive multi-omics analysis. Transcriptome and miRnome comparisons combined with protein analyses at 7 time points demonstrate that hiPSC differentiation 1) mimics described DMD phenotypes at the differentiation endpoint; and 2) homogeneously and robustly recapitulates key developmental steps - mesoderm, somite, skeletal muscle - which offers the possibility to explore dystrophin functions and find earlier disease biomarkers. Starting at the somite stage, mitochondrial gene dysregulations escalate during differentiation. We also describe fibrosis as an intrinsic feature of skeletal muscle cells that starts early during myogenesis. In sum, our data strongly argue for an early developmental manifestation of DMD whose onset is triggered before the entry into the skeletal muscle compartment, data leading to a necessary reconsideration of dystrophin functions during muscle development.

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miR-486 is an epigenetic modulator of Duchenne muscular dystrophy pathologies [RNA-seq]

Project description:Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle disorder resulting in muscle weakness and cardiomyopathy. MicroRNAs have shown to play a significant role 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. miR-486 knockout mice developed disrupted myofiber architecture, decreased myofiber size, decreased locomotor activity, increased 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. 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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Analysis of skeletal muscle from a tailored pig model of Duchenne muscular dystrophy

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Jarrah2014 - mathematical model of the immune response in muscle degeneration and subsequent regeneration in Duchenne muscular dystrophy in mdx mice

Project description:Duchenne muscular dystrophy (DMD) is a genetic disease that results in the death of affected boys by early adulthood.The genetic defect responsible for DMD has been known for over 25 years, yet at present there is neither cure nor effective treatment for DMD. During early disease onset, the mdx mouse has been validated as an animal model for DMD and use of this model has led to valuable but incomplete insights into the disease process. For example, immune cells are thought to be responsible for a significant portion of muscle cell death in the mdx mouse; however, the role and time course of the immune response in the dystrophic process have not been well described. In this paper we constructed a simple mathematical model to investigate the role of the immune response in muscle degeneration and subsequent regeneration in the mdx mouse model of Duchenne muscular dystrophy. Our model suggests that the immune response contributes substantially to the muscle degeneration and regeneration processes. Furthermore, the analysis of the model predicts that the immune system response oscillates throughout the life of the mice, and the damaged fibers are never completely cleared.

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