DMD vs. AGING
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE32720 | GEO | 2011/11/01
SECONDARY ACCESSION(S): PRJNA146791
REPOSITORIES: GEO
Similar Datasets
Project description:Comparative effects of Duchenne Muscular Dystrophy (DMD) and Aging in skeletal muscle Expression profiling established by microarray technology provides a powerful tool by which complex pathways can be assembled. The pathophysiology of Duchenne Muscular Dystrophy (DMD) is a complex process involving many pathways downstream of the primary genetic insult (lack of dystrophin). Similarly, the mechanisms implicated in muscle aging are only partially understood. The objective of the present study was to compare the muscle transcriptional response downstream of lack of dystrophin with the molecular events associated with aging using a muscle-dedicated microarray. Defining a common transcriptional profile in a range of wasting diseases should increase our understanding of the critical adaptations associated with muscle atrophy independent of the cause of the muscle wasting. RNA samples from 4 DMD and 4 AGE skeletal muscle tissues were analyzed by hybridization against control samples. This hybridization was done on microarrays containing quadruplicate 50-mer oligonucleotides corresponding to 3,588 muscle relevant genes. Two hybridizations were per-formed for each subject. Thus, eight values per gene were obtained for each subject. These stringent conditions conferred powerful significance to our results.
2011-11-01 | E-GEOD-32720 | biostudies-arrayexpress
Project description:Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked dystrophin (DMD) gene. The absence of dystrophin protein leads to progressive muscle weakness and wasting, disability and death. To establish a tailored large animal model of DMD, we deleted DMD exon 52 in male pig cells by gene targeting and generated offspring by nuclear transfer. DMD pigs exhibit absence of dystrophin in skeletal muscles, increased serum creatine kinase levels, progressive dystrophic changes of skeletal muscles, impaired mobility, muscle weakness, and a maximum life span of 3 months due to respiratory impairment. To address the accelerated development of muscular dystrophy in DMD pigs as compared to human patients, we performed a genome-wide transcriptome study of M. biceps femoris samples from 2-day-old and 3-month-old DMD and age-matched wild-type pigs. The transcriptome changes in 3-month-old DMD pigs were in good accordance with the findings of gene expression profiles in human DMD, reflecting the processes of degeneration, regeneration, inflammation, fibrosis, and impaired metabolic activity. The transcriptome profile of 2-day-old DMD pigs pointed towards increased protein and DNA catabolism, reduced extracellular matrix formation and cell proliferation and showed similarities with transcriptome changes induced by exercise injury in muscle. Our transcriptome studies provide new insights into congenital changes associated with dystrophin deficiency and secondary complications arising during postnatal development. Thus the DMD pig is a useful model to determine the hierarchy of physiological derangements in dystrophin-deficient muscle. 13 samples, two conditions, two age-groups, 3-4 biological replicates
2013-08-06 | E-GEOD-44096 | biostudies-arrayexpress
Project description:Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the dystrophin (DMD) gene, leading to the complete absence of DMD and progressive degeneration of skeletal and heart muscles. Expression of an internally shortened dystrophin in DMD subjects (DMDΔ52) can be achieved by skipping DMD exon 51 to reframe the transcript. To predict the best possible outcome of this therapeutic strategy, we generated transgenic pigs lacking DMD exon 51 and 52, additionally representing a new model for Becker muscular dystrophy (BMD). To inspect the proteome alterations caused by the different dystrophin mutations in an unbiased and comprehensive manner, we performed a label-free liquid chromatography-tandem mass spectrometry analysis (LC-MS/MS) of myocardial and skeletal muscle samples from wild-type (WT), DMDΔ52 and DMDΔ51-52 pigs.
2023-07-11 | PXD039533 | Pride
Project description:Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked dystrophin (DMD) gene. The absence of dystrophin protein leads to progressive muscle weakness and wasting, disability and death. To establish a tailored large animal model of DMD, we deleted DMD exon 52 in male pig cells by gene targeting and generated offspring by nuclear transfer. DMD pigs exhibit absence of dystrophin in skeletal muscles, increased serum creatine kinase levels, progressive dystrophic changes of skeletal muscles, impaired mobility, muscle weakness, and a maximum life span of 3 months due to respiratory impairment. To address the accelerated development of muscular dystrophy in DMD pigs as compared to human patients, we performed a genome-wide transcriptome study of M. biceps femoris samples from 2-day-old and 3-month-old DMD and age-matched wild-type pigs. The transcriptome changes in 3-month-old DMD pigs were in good accordance with the findings of gene expression profiles in human DMD, reflecting the processes of degeneration, regeneration, inflammation, fibrosis, and impaired metabolic activity. The transcriptome profile of 2-day-old DMD pigs pointed towards increased protein and DNA catabolism, reduced extracellular matrix formation and cell proliferation and showed similarities with transcriptome changes induced by exercise injury in muscle. Our transcriptome studies provide new insights into congenital changes associated with dystrophin deficiency and secondary complications arising during postnatal development. Thus the DMD pig is a useful model to determine the hierarchy of physiological derangements in dystrophin-deficient muscle.
2013-08-06 | GSE44096 | GEO
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.
2023-07-20 | GSE235673 | GEO
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.
2021-12-01 | PXD027772 | Pride
Project description:Duchenne Muscular Dystrophy (DMD) is a fatal muscle wasting disorder caused by dystrophin deficiency. Previous work suggested that increased expression of the dystrophin-related protein utrophin in the mdx mouse model of DMD can prevent dystrophic pathophysiology. Physiological tests showed that the transgenic mouse muscle functioned in a way similar to normal muscle. More recently, it has become possible to analyse disease pathways using microarrays, a sensitive method to evaluate the efficacy of a therapeutic approach. We thus examined the gene expression profile of mdx mouse muscle compared to normal mouse muscle and compared the data with that obtained from the transgenic line expressing utrophin. The data confirm that the expression of utrophin in the mdx mouse muscle results in a gene expression profile virtually identical to that seen for the normal mouse. This study confirms that a strategy to up-regulate utrophin is likely to be effective in preventing the disease. Experiment Overall Design: Here we have addressed important question of changes in the global gene expression profile of mdx mouse muscle compared to normal mouse muscle and compared the data with that obtained from the transgenic line (fiona) expressing high level of utrophin on mdx background.
2008-06-15 | E-GEOD-7187 | biostudies-arrayexpress
Project description:Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disorder caused by mutations in the Dystrophin gene with no therapeutic option. To bridge the gap between preclinical and therapeutic evaluation studies, we have generated a rat model for DMD that carries an exon 52 deletion (R DMDdel52) causing a complete lack of dystrophin protein. Here we show that R DMDdel52 animals recapitulated human DMD pathophysiological trajectory more faithfully than the mdx mouse model. We report that R DMDdel52 rats displayed progressive and severe skeletal muscle loss associated with fibrotic deposition, fat infiltration and fibre type switch. Early fibrosis was also apparent in the cardiac muscle. These histological modifications led to severe muscle, respiratory and cardiac functional impairments leading to premature death around one year. Moreover, DMD muscle exhibited systemic inflammation with a mixed M1/M2 phenotype. A comparative single cell RNAseq analysis of the diaphragm muscle was performed, revealing cellular populations alteration and molecular modifications in all muscle cell types. We show that DMD fibroadipogenic progenitors produced elevated levels of cartilage oligomeric matrix protein (COMP), a glycoprotein responsible for modulating homeostasis of extracellular matrix, and whose increased concentration correlated with muscle fibrosis both in R DMDdel52 rats and human patients. Fibrosis is a component of tissue remodelling impacting the whole musculature of DMD patients, at the tissue level but most importantly at the functional level. We therefore propose that this specific biomarker can optimize the prognostic monitoring of functional improvement of patients included in clinical trials.
2022-03-14 | GSE198237 | GEO
Project description:Duchenne Muscular Dystrophy (DMD) is a fatal muscle wasting disorder caused by dystrophin deficiency. Previous work suggested that increased expression of the dystrophin-related protein utrophin in the mdx mouse model of DMD can prevent dystrophic pathophysiology. Physiological tests showed that the transgenic mouse muscle functioned in a way similar to normal muscle. More recently, it has become possible to analyse disease pathways using microarrays, a sensitive method to evaluate the efficacy of a therapeutic approach. We thus examined the gene expression profile of mdx mouse muscle compared to normal mouse muscle and compared the data with that obtained from the transgenic line expressing utrophin. The data confirm that the expression of utrophin in the mdx mouse muscle results in a gene expression profile virtually identical to that seen for the normal mouse. This study confirms that a strategy to up-regulate utrophin is likely to be effective in preventing the disease. Keywords: Global gene expression profile
2008-04-23 | GSE7187 | GEO
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 were investigated in order to confirm muscular fibrosis and MSOT signals.
2020-01-09 | PXD016003 | Pride