Expression data from cerivastatin-treated rat skeletal muscle
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE4418 | GEO | 2007/03/05
SECONDARY ACCESSION(S): PRJNA94731
REPOSITORIES: GEO
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Project description:Adverse effects of statins include skeletal muscle toxicity; Type II glycolytic fibers are more senstive to statin damage; exercise exacerbates statin muscle degeneration. We used a well-characterized rat model of statin-induced muscle degeneration, at which 1.0 mg/kg/day (high dose) cerivastatin produces mild to moderate histological degeneration. We used microarrays to detail the global programme of gene expression underlying cerivastatin effects on rat gastrocnemius and soleus muscles, as well as the effect of cerivastatin combined with treadmill exercise. We identified distinct classes of up- and down-regulated genes during this process. Experiment Overall Design: We treated female SD rats with vehicle or 3 doses of cerivastatin (0.1, 0.5, 1.0 mg/kg/day) for 14 days, plus or minus 5 days/week of exercise on treadmills (20 min/day at 20 m/min). Gastrocnemius and soleus muscle samples were harvested for RNA extraction and hybridization on Affymetrix microarrays. A total of 12 samples were analyzed with 3-4 biological replicates per sample. Our goals were to determine 1) the effect of cerivastatin; 2) the effect of exercise combined with cerivastatin; 3) an explanation for the muscle fiber type sensitivity to statins. Since all doses of cerivastatin had no effect on soleus muscle (PubMed ID: 16141437), we analysed samples from soleus from control and high dose groups only.
2008-06-13 | E-GEOD-4418 | biostudies-arrayexpress
Project description:Statin-induced myopathy is a common side-effect but its mechanisms in human skeletal muscle have never been explained satisfyingly. We exposed 25 different primary human muscle cell lines to either a lipophilic or a hydrophilic statin, quantified cholesterol, mevalonate, proliferation, differentiation, and performed a comprehensive transcriptome and proteome analysis. We found reduced mevalonic acid (MVA) and cholesterol levels demonstrating incorporation of statins into the cells. Statins also significantly impaired proliferation and differentiation. Using an integrated pathway analysis approach with transcriptome and proteome data from statin-treated human primary myotubes, we modelled a novel statin-induced metabolism network for human muscle cells. This analysis confirmed the effect of statins on cholesterol biosynthesis but also uncovered alterations of acetyl CoA-dependent lipid and fatty acid metabolism
2020-02-24 | GSE107998 | GEO
Project description:Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of patients taking statins experience muscle related adverse events. Myalgia, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels, is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin-associated myalgia are not clearly understood. To elucidate changes in gene expression associated with statin-induced myalgia, we compared profiles of gene expression in the biopsied skeletal muscle from statin-intolerant patients undergoing statin re-challenge versus those of statin-tolerant controls. A robust separation of statin-intolerant and statin-tolerant cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of statin intolerant patients, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals are genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario further bolstered by the discovery that a number of single nucleotide polymorphisms (e.g., SLCO1B1, SLCO2B1 and RYR2) associated with statin myopathy were observed with increased frequency among statin-intolerant study subjects.
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Project description:Global gene expression of the rat soleus muscle was assessed with microarrays after 12 hrs of physical inactivity and also after 12 hours of physical inactivity immediately followed by 2 hrs treadmill walking and compared to normally caged rats with voluntary standing and intermittent cage movements. Experiment Overall Design: Rats were either prevented from standing on the their hindlimbs for 12 hrs or were prevented from standing on the their hindlimbs for 12 hrs and then immediately engaged in 2 hours treadmill walking and compared to caged rats with normal standing/ambulatory activity. RNA was extracted from soleus muscles and each array represents the pooling of the RNA from the soleus of 8-10 different rats.
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Project description:Global gene expression of the rat soleus muscle was assessed with microarrays after 12 hrs of physical inactivity and also after 12 hours of physical inactivity immediately followed by 2 hrs treadmill walking and compared to normally caged rats with voluntary standing and intermittent cage movements. Keywords: between group design
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Project description:Epidemiological studies reveal a strong link between low aerobic capacity and metabolic and cardiovascular diseases. Two-way artificial selection of rats based on low and high intrinsic exercise capacity has produced two strains that also differ in risk for metabolic syndrome (Koch LG, Britton SL. Artificial selection for intrinsic aerobic endurance running capacity in rats. Physiol Genomics 5:45-52, 2001). Here we investigated skeletal muscle characteristics and genotype-phenotype relationships behind high and low inherited aerobic exercise capacity and the link between oxygen metabolism and metabolic disease risk factors in rats derived from generation 18. This population (n=24) of high capacity runners (HCR) and low capacity runners (LCR) differed by 615% in maximal treadmill running capacity. LCR were significantly significantly heavier and had increased blood glucose, serum insulin and triglyceride concentration. HCR had higher resting metabolic rate than LCR. Capillaries/mm2 and capillary-to-fiber ratio were significantly greater in HCR rats in soleus and gastrocnemius and capillary-to-fiber ratio in extensor digitorum longus (EDL) muscle. Subsarcolemmal mitochondrial area was 96% (p<0.01) and intermyofibrillar area was 32% (p<0.05) larger in HCR soleus. Microarray results showed that 126 genes were significantly up-regulated and 113 genes were down-regulated in HCR (p<0.05). Functional clustering and unbiased correlation analysis of muscle microarray data revealed that genes up-regulated in HCR were related to mitochondria, carboxylic acid and lipid metabolism, and oxidoreductase activity. In conclusion, our data show that aerobic capacity is strongly linked to the architecture of energy transfer and corroborate the importance of oxygen metabolism as the determinant of metabolic health and complex metabolic diseases such as metabolic syndrome and type 2 diabetes. Total RNA obtained from gastrocnemius muscle was compared between rat strains of low and high inherited aerobic exercise capacity.
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Project description:Clinical data of patients suffering from COVID-19 have indicated that statin therapy, used to treat hypercholesterolemia, is associated with a better clinical outcome. We therefore investigated the effect of statins on SARS-CoV-2 infection in human lung cells and found that fluvastatin inhibited coronavirus infection, while other tested statins did not. Fluvastatin inhibited high and low pathogenic coronaviruses in vitro and ex vivo in a dose-dependent manner. Proteomic analyses of infected versus uninfected lung epithelial cells treated with fluvastatin, simvastatin, or rosuvastatin revealed that all tested statins modulated the cholesterol synthesis pathways without compromising the innate antiviral immune response. Strikingly, fluvastatin treatment uniquely affected the proteome of SARS CoV 2 infected cells, specifically downregulating proteins that modulate protein translation and viral replication. These results suggest that statin therapy poses no additional risk to individuals exposed to SARS-CoV-2 and that fluvastatin may have a moderate beneficial effect on SARS CoV-2 infection by modulating protein translation.
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