Unknown,Transcriptomics,Genomics,Proteomics

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Hypoxic endurance exercise in an untrained or six weeks trained state

ABSTRACT: Time course of mRNA after 30 minutes of endurance exercise at simulated altitude of 4000 m in an untrained or six weeks trained state of six subjects. Time course of mRNA after 30 minutes of endurance exercise at simulated altitude of 4000 m in an untrained (1) or six weeks trained state (2) of six subjects (Hoxxx) Ho981: (1) GSM343213, GSM343214, GSM343215, GSM343216; (2) GSM343217, GSM343218, GSM343219, GSM343220 Ho982: (1) GSM343221, GSM343222, GSM343223, GSM343224; (2) GSM343225, GSM343226, GSM343227, GSM343228 Ho984: (1) GSM343229, GSM343230, GSM343231, GSM343232; (2) GSM343233, GSM343234, GSM343235, GSM343236 Ho994: (1) GSM343237, GSM343238, GSM343239, GSM343240; (2) GSM343241, GSM343242, GSM343243, GSM343244 Ho998: (1) GSM343245, GSM343246, GSM343247, GSM343248; (2) GSM343249, GSM343250, GSM343251, GSM343252 Ho996: (1) GSM343253, GSM343254, GSM343255, GSM343256 Keywords: time-course

ORGANISM(S): Homo sapiens

SUBMITTER: Martin Flück

PROVIDER: E-GEOD-13623 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:This study was undertaken to test the hypothesis that short term exposure (4 hours) to physiologic hyperinsulinemia in normal, healthy subjects without a family history of diabetes would induce a low grade inflammatory response, independently of glycemic status. We performed euglycemic hyperinsulinemic (80 mU/m2/min) clamps in 12 healthy, insulin sensitive subjects with no family history of diabetes followed by biopsies of the vastus lateralis muscle taken basally and after 30 and 240 minutes of insulin infusion. Gene expression profiles were generated using Affymetrix HG-U133A arrays. No probe sets had significantly altered expression at 30 minutes of the insulin clamp, but 121 probe sets (117 upregulated and 4 downregulated) were significantly altered after 240 minutes. Hyperinsulinemia in normal, healthy human subjects increased the mRNAs for a number of inflammatory genes and transcription factors. Microarray and quantitative RT-PCR revealed the upregulation of chemokine, cc motif, ligand 2 (CCL2), CCL8, thrombomodulin (THBD), ras-related associated with diabetes (RRAD), metallothionein (MT), and serum/glucocorticoid regulated kinase (SGK), and downregulation of CITED2 (a CREB-binding protein-interacting transactivator), a known coactivator of PPAR-alpha. Interestingly, SGK and CITED2 are located at chromosome 6q23, where we previously detected strong linkage to hyperinsulinemia. A control saline infusion performed on 3 normal, healthy subjects without a family history of diabetes demonstrated that the genes altered following the euglycemic-hyperinsulinemic clamp were due to insulin and independent of biopsy removal. This study demonstrates that insulin acutely regulates the expression of genes involved in inflammation and transcription, and identifies several candidate genes/pathways for further investigation. Experiment Overall Design: Twelve subjects received a vastus lateralis muscle biopsy followed by a 180-min euglycemic, hyperinsulinemic (80 mU/m2.min) clamp. Muscle biopsies from each subject were homogenized in RNAStat solution (Tel-Test Inc., Friendswood, TX), using a Polytron homogenizer (Brinkmann Instruments Westbury, NY). Total RNA was purified with RNeasy and DNase I treatment (Qiagen, Chatsworth, CA). RNA was prepared for hybridization to Affymetrix (Santa Clara, CA) HG-U133A arrays according to the manufacturerâs instructions.

Project description:Septic patients treated in the intensive care unit (ICU) often develop multiple organ failure including persistent skeletal muscle dysfunction which results in the patientâs protracted recovery process. We have demonstrated that muscle mitochondrial enzyme activities are impaired in septic ICU patients resulting in decreased cellular energy which will interfere with muscle function and metabolism. Here we use detailed phenotyping and genomics to elucidate mechanisms leading to these impairments. Methodology/Principle Findings Utilising biopsy material from seventeen patients and ten age-matched controls we demonstrate that neither mitochondrial in vivo protein synthesis nor expression of mitochondrial genes are compromised. Indeed, there was partial activation of the mitochondrial biogenesis pathway involving NRF2?/GABP and its target genes TFAM, TFB1M and TFB2M yet clearly this failed to maintain mitochondrial function. We therefore utilised transcript profiling and pathway analysis of ICU patient skeletal muscle to generate insight into the molecular defects driving loss of muscle function and metabolic homeostasis. Gene ontology analysis of Affymetrix analysis demonstrated substantial loss of muscle specific genes, a global oxidative stress response related to most probably cytokine signalling, altered insulin related signalling and a substantial overlap between patients and muscle wasting/inflammatory animal models. MicroRNA 21 processing appeared defective suggesting that post-transcriptional protein synthesis regulation is altered by disruption of tissue microRNA expression. Finally, we were able to demonstrate that the phenotype of skeletal muscle in ICU patients is not merely one of inactivity, it appears to be an actively remodelling tissue, influenced by several mediators, all of which may be open to manipulation with the aim to improve clinical outcome. Conclusions/Significance This first combined protein and transcriptome based analysis of human skeletal muscle obtained from septic patients demonstrated that losses of mitochondria and muscle mass are accompanied by sustained protein synthesis (anabolic process) while dysregulation of transcription programmes appears to fail to compensate for increased damage and proteolysis. Our analysis identified both validated and novel clinically tractable targets to manipulate these failing processes and pursuit of these could lead to new potential treatments. Experiment Overall Design: 13 septic samples, 8 controls

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Hypoxic endurance exercise in an untrained or six weeks trained state

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