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Proteome- and Transcriptome-Driven Reconstruction of the Human Myocyte Metabolic Network and Its Use for Identification of Markers for Diabetes
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2015 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 11, no 6, p. 921-933Article in journal (Refereed) Published
Abstract [en]

Skeletal myocytes are metabolically active and susceptible to insulin resistance and are thus implicated in type 2 diabetes (T2D). This complex disease involves systemic metabolic changes, and their elucidation at the systems level requires genome-wide data and biological networks. Genome-scale metabolic models (GEMs) provide a network context for the integration of high-throughput data. We generated myocyte-specific RNA-sequencing data and investigated their correlation with proteome data. These data were then used to reconstruct a comprehensive myocyte GEM. Next, we performed a meta-analysis of six studies comparing muscle transcription in T2D versus healthy subjects. Transcriptional changes were mapped on the myocyte GEM, revealing extensive transcriptional regulation in T2D, particularly around pyruvate oxidation, branched-chain amino acid catabolism, and tetrahydrofolate metabolism, connected through the downregulated dihydrolipoamide dehydrogenase. Strikingly, the gene signature underlying this metabolic regulation successfully classifies the disease state of individual samples, suggesting that regulation of these pathways is a ubiquitous feature of myocytes in response to T2D.

Place, publisher, year, edition, pages
2015. Vol. 11, no 6, p. 921-933
Keyword [en]
Gene-Set Analysis, Insulin-Resistance, Skeletal-Muscle, Expression Data, Oxidative-Phosphorylation, Amino-Acids, Integration, Obesity, Quantification, Hyperglycemia
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:kth:diva-169267DOI: 10.1016/j.celrep.2015.04.010ISI: 000354406900009PubMedID: 25937284OAI: oai:DiVA.org:kth-169267DiVA, id: diva2:821457
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg FoundationNovo Nordisk
Note

QC 20150615

Available from: 2015-06-15 Created: 2015-06-12 Last updated: 2017-12-04Bibliographically approved

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Uhlén, Mathias

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