Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA232687 | ENA |
REPOSITORIES: ENA
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Project description:Objectives: Systemic inflammation is a major risk factor for critical-illness myopathy (CIM) but its pathogenic role in muscle is uncertain. We observed that interleukin 6 (IL-6) and serum amyloid A1 (SAA1) expression was upregulated in muscle of critically ill patients. To test the relevance of these responses we assessed inflammation and acute-phase response at early and late time points in muscle of patients at risk for CIM. Design: Prospective observational clinical study and prospective animal trial. Setting: Two intensive care units (ICU) and research laboratory. Patients/Subjects: 33 patients with Sequential Organ Failure Assessment scores ≥8 on 3 consecutive days within 5 days in ICU were investigated. A subgroup analysis of 12 patients with, and 18 patients without CIM (non-CIM) was performed. Two consecutive biopsies from vastus lateralis were obtained at median days 5 and 15, early and late time points. Controls were 5 healthy subjects undergoing elective orthopedic surgery. A septic mouse model and cultured myoblasts were used for mechanistic analyses. Measurements and Main Results: Early SAA1 expression was significantly higher in skeletal muscle of CIM compared to non-CIM patients. Immunohistochemistry showed SAA1 accumulations in CIM patients at the early time point, which resolved later. SAA1 expression was induced by IL-6 and tumor necrosis factor-alpha in human and mouse myocytes in vitro. Inflammation-induced muscular SAA1 accumulation could be reproduced in a sepsis mouse model. Conclusions: Skeletal muscle contributes to general inflammation and acute-phase response in CIM patients. Muscular SAA1 could be important for CIM pathogenesis. Trial registration: ISRCTN77569430. Expression analysis of patients with and without CIM (non-CIM) was performed. Date were quantile normalized using Partek Genomic Suite 6.5, RMA background correction, pre background adjustment for GC content and data were limited to the full dataset
2014-05-06 | E-GEOD-53702 | biostudies-arrayexpress
Project description:Objectives: Systemic inflammation is a major risk factor for critical-illness myopathy (CIM) but its pathogenic role in muscle is uncertain. We observed that interleukin 6 (IL-6) and serum amyloid A1 (SAA1) expression was upregulated in muscle of critically ill patients. To test the relevance of these responses we assessed inflammation and acute-phase response at early and late time points in muscle of patients at risk for CIM. Design: Prospective observational clinical study and prospective animal trial. Setting: Two intensive care units (ICU) and research laboratory. Patients/Subjects: 33 patients with Sequential Organ Failure Assessment scores ≥8 on 3 consecutive days within 5 days in ICU were investigated. A subgroup analysis of 12 patients with, and 18 patients without CIM (non-CIM) was performed. Two consecutive biopsies from vastus lateralis were obtained at median days 5 and 15, early and late time points. Controls were 5 healthy subjects undergoing elective orthopedic surgery. A septic mouse model and cultured myoblasts were used for mechanistic analyses. Measurements and Main Results: Early SAA1 expression was significantly higher in skeletal muscle of CIM compared to non-CIM patients. Immunohistochemistry showed SAA1 accumulations in CIM patients at the early time point, which resolved later. SAA1 expression was induced by IL-6 and tumor necrosis factor-alpha in human and mouse myocytes in vitro. Inflammation-induced muscular SAA1 accumulation could be reproduced in a sepsis mouse model. Conclusions: Skeletal muscle contributes to general inflammation and acute-phase response in CIM patients. Muscular SAA1 could be important for CIM pathogenesis. Trial registration: ISRCTN77569430.
2014-05-06 | GSE53702 | GEO
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant condition that is characterised by a progressive degeneration and weakness of skeletal muscle fibers. The underlying cause of FSHD has been attributed to inappropriate expression of the transcription factor double homeobox (Dux); however, the mechanisms leading to myopathy in response to Dux expression remain incompletely understood. To study the acute effects of Dux activation in mammalian skeletal muscle fibers, we generated a recombinant adeno-associated viral vector allowing tunable Dux expression. Consistent with previous findings, we confirmed that the ectopic expression of Dux in mouse skeletal muscle results in a degenerative myopathy. Building on these findings, we observed that the acute expression of Dux in muscle fibers causes profound transcriptome changes prior to the onset of pathology. Furthermore, muscles expressing Dux display elevated levels of the TGF-beta superfamily member, Myostatin and increased Smad2/3 activity. Notably, inhibition of Myostatin is sufficient to prevent Dux-induced myopathy. Collectively, these findings support further investigation of interventions targeting the Myostatin-Smad2/3 pathway as prospective approaches to treating myopathy associated with Dux mis-expression.
2021-12-31 | GSE108828 | GEO
Project description:Acute quadriplegic myopathy (AQM) or critical illness myopathy (CIM) is frequently observed in intensive care unit (ICU) patients. In order to elucidate duration-dependent effects of the ICU intervention on molecular and functional networks that control the muscle wasting and weakness in AQM, gene expression profile was analyzed at time points varying from 6 hours to 14 days in a unique experimental rat model mimicking ICU conditions, i.e., post-synaptically paralyzed, mechanically ventilated and extensively monitored animals.
2011-07-23 | GSE30848 | GEO
Project description:Summary: Genetic disorders of muscle cause muscular dystrophy, and are some of the most common inborn errors of metabolism. Muscle also rapidly remodels in response to training and innervation. Muscle weakness and wasting is important in such conditions as aging, critical care medicine, space flight, and diabetes. Finally, muscle can also be used to investigate systemic defects, and the compensatory mechansisms invoked by cells to overcome biochemical and genetic abnormalities. Here, we provide a 13 group data set for comparative profiling of human skeletal muscle. Groups studied are: Normal human skeletal muscle, Acute quadriplegic myopathy (AQM; critical care myopathy), Juvenile dermatomyositis (JDM), Amyotophic lateral sclerosis (ALS), spastic paraplegia (SPG4; spastin), Fascioscapulohumeral muscular dystrophy (FSHD), Emery Dreifuss muscular dystrophy (both X linked recessive emerin form; autosomal dominant Lamin A/C form), Becker muscular dystrophy (partial loss of dystrophin), Duchenne muscular dystrophy (complete loss of dystrophin), Calpain 3 (LGMD2A), dysferlin (LGMD2B), FKRP (glycosylation defect; homozygous for a missense mutation). U133A and U133B microarrays are both available. Hypothesis: This data set is able to define biochemical pathways that are either specific for a disease group, or shared between disease groups. For example, this data set has been used to determine the biochemical pathway perturbations that are shared between the two different types of Emery Dreifuss muscular dystrophy (lamin A/C, and emerin). Specific Aim: The specific aim of this study is to determine the disease-specific transcriptional profiles of these 13 patient groups, and to determine if these expression fingerprints provide either pathophysiology or diagnostic information for these diseases. Some of the groups in this large data set have been reported previously using U95A microarrays, as follows: Juvenile dermatomyositis (JDM): Tezak Z, Hoffman EP, Lutz JL, Fedczyna TO, Stephan D, Bremer EG, Krasnoselska-Riz I, Kumar A, Pachman LM. Gene expression profiling in DQA1*0501+ children with untreated dermatomyositis: a novel model of pathogenesis. J Immunol. 2002 Apr 15;168(8):4154-63. PMID: 11937576 Duchenne muscular dystrophy (DMD) Chen YW, Zhao P, Borup R, Hoffman EP. Expression profiling in the muscular dystrophies: identification of novel aspects of molecular pathophysiology. J Cell Biol. 2000 Dec 11;151(6):1321-36. PMID: 11121445 Spastic paraplegia (SPG4, spastin): Molon A, Di Giovanni S, Chen YW, Clarkson PM, Angelini C, Pegoraro E, Hoffman EP. Large-scale disruption of microtubule pathways in morphologically normal human spastin muscle. Neurology. 2004 Apr 13;62(7):1097-104. PMID: 15079007 Acute quadriplegic myopathy (AQM): Di Giovanni S, Molon A, Broccolini A, Melcon G, Mirabella M, Hoffman EP, Servidei S. Constitutive activation of MAPK cascade in acute quadriplegic myopathy. Ann Neurol. 2004 Feb;55(2):195-206. PMID: 14755723 Fascioscapulohumeral muscular dystrophy (FSHD): Winokur ST, Chen YW, Masny PS, Martin JH, Ehmsen JT, Tapscott SJ, van der Maarel SM, Hayashi Y, Flanigan KM. Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation. Hum Mol Genet. 2003 Nov 15;12(22):2895-907. Epub 2003 Sep 30. PMID: 14519683 Keywords: muscle disease comparison Groups studied are: Normal human skeletal muscle, Acute quadriplegic myopathy (AQM; critical care myopathy), Juvenile dermatomyositis (JDM), Amyotophic lateral sclerosis (ALS), spastic paraplegia (SPG4; spastin), Fascioscapulohumeral muscular dystrophy (FSHD), Emery Dreifuss muscular dystrophy (both X linked recessive emerin form; autosomal dominant Lamin A/C form), Becker muscular dystrophy (partial loss of dystrophin), Duchenne muscular dystrophy (complete loss of dystrophin), Calpain 3 (LGMD2A), dysferlin (LGMD2B), FKRP (glycosylation defect; homozygous for a missense mutation).
2005-10-14 | E-GEOD-3307 | biostudies-arrayexpress
Project description:Acute quadriplegic myopathy (AQM) or critical illness myopathy (CIM) is frequently observed in intensive care unit (ICU) patients. In order to elucidate duration-dependent effects of the ICU intervention on molecular and functional networks that control the muscle wasting and weakness in AQM, gene expression profile was analyzed at time points varying from 6 hours to 14 days in a unique experimental rat model mimicking ICU conditions, i.e., post-synaptically paralyzed, mechanically ventilated and extensively monitored animals. A total of five sham operated controls and 23 experimental female Sprague-Dawley rats were included in this study. The experimental rats were anaesthetized, treated with the neuromuscular blocker (NMBA), α-cobrotoxin, mechanically ventilated and monitored for durations varying from 6h to 4 days (n=13), from 5 to 9 days (n=4), and from 9 to 14 days (n=6). Muscle biopsies were obtained from gastrocnemius muscle (proximal part) immediately after euthanasia and were quickly frozen in liquid propane cooled by liquid nitrogen, and stored at -80°C.RNA was extracted.
2011-07-22 | E-GEOD-30848 | biostudies-arrayexpress
Project description:Skeletal muscle fiber composition and muscle energetics are not static and change in muscle disease. This study was performed to determine if a mitochondrial myopathy is associated with adjustments in skelatal fiber type composition. These effects of drug induced mitochondrial dysfunction on skeletal muscle fiber type composition were analyzed in an animal model.
2012-10-18 | E-MEXP-3642 | biostudies-arrayexpress
Project description:<p>Severe myopathic events occur in 0.1-0.5% of patients taking statins. Although genetic association studies have identified some possibly associated gene loci, these have not been reproducible in additional studies with independent patient cohorts. A more reasonable explanation for susceptibility to statin-induced myopathy is the presence of rare pathogenic variants in genes important for skeletal muscle structure and function. In support of this, we have previously reported an increased incidence of pathogenic variants in genes causing metabolic myopathies in patients with statin-induced myopathy (<a href="https://www.ncbi.nlm.nih.gov/pubmed/16671104">Vladutiu et al.</a>,2006). We also reported a patient with statin myopathy who had an <i>RYR1</i> variant known to be causative of malignant hyperthermia susceptibility (MHS) (<a href="https://www.ncbi.nlm.nih.gov/pubmed/21795085">Vladutiu et al.</a>, 2011). There are a number of genes associated with metabolic myopathies triggered by various factors such as extreme exercise, fasting, extremes in temperature, viral infection and exposure to volatile anesthetics. In addition, many of the genes causing congenital myopathies, myofibrillar myopathies and muscular dystrophies have overlapping phenotypes with these genes. We propose that statins act as an additional trigger inducing myopathic symptoms and many patients with severe statin-induced myopathy have causative genetic variants within similar genes associated with MHS and congenital myopathy. We have analyzed the resultant data using a disease model in which rare pathogenic variants, possibly within multiple genes, are causative of statin-induced myopathy. In this study, we have identified potentially causative genetic variants in greater than 50% of the statin-induced myopathy cases and in particular, rare and possibly pathogenic in the RYR1 and CACNA1S genes were present in 25% of the patient samples studied. Vladutiu, G. D., Simmons, Z., Isackson, P.J., Tarnopolsky, M., Peltier, W.L., Barboi, A.C., Sripathi, N., Wortmann, R.L., Phillips, P.S., (<a href="https://www.ncbi.nlm.nih.gov/pubmed/16671104">2006</a>). "Genetic risk factors associated with lipid-lowering drug-induced myopathies." Muscle Nerve 34: 153-162. Vladutiu, G. D., Isackson, P.J., Kaufman, K., Harley, J.B., Cobb, B., Christopher-Stine, L., Wortmann, R.L, (<a href="https://www.ncbi.nlm.nih.gov/pubmed/21795085">2011</a>). "Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies." Mol Genet Metab 104: 167-173. </p>
| phs001342 | dbGaP
Project description:Progressive mitochondrial respiratory chain (RC) deficiency is associated with a wide spectrum of adult-onset degenerative diseases, as well as with normal aging. We have previously generated the Deletor mice to model late-onset progressive RC defects. Here we report novel tissue-specific pathways contributing to mitochondrial disease pathogenesis, identified by gene expression analysis. We found that RC-deficient muscle fibers secrete the fasting-induced hormone, fibroblast growth factor 21 (FGF21). This response leads to fatty acid recruitment from adipocytes and resistance to high-fat-diet induced obesity in mice, but does not affect glucose or insulin metabolism. FGF21 is also induced in the muscle of mitochondrial myopathy patients and in other RC-deficient mice. These data show that skeletal muscle is an endocrine organ, which signals its energy deficiency through FGF21. Furthermore, RC deficiency in single muscle fibers initiates a global starvation response. These data have important implications for conditions with primary or secondary RC deficiency. Mice overexpressing mutant Twinkle (C10ORF2) protein are the first animal model for Progressive External Ophtalmoplegia (PEO). Using PEO-model and wt-mice, skeletal muscle (quadriceps femoris) was analyzed for gene expression profile.
2011-11-16 | E-GEOD-18119 | biostudies-arrayexpress