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Type 2 diabetes and obesity induce similar transcriptional reprogramming in human myocytes
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2017 (English)In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 9, 47Article in journal (Refereed) Published
Abstract [en]

Background: Skeletal muscle is one of the primary tissues involved in the development of type 2 diabetes (T2D). The close association between obesity and T2D makes it difficult to isolate specific effects attributed to the disease alone. Therefore, here we set out to identify and characterize intrinsic properties of myocytes, associated independently with T2D or obesity. Methods: We generated and analyzed RNA-seq data from primary differentiated myotubes from 24 human subjects, using a factorial design (healthy/T2D and non-obese/obese), to determine the influence of each specific factor on genome-wide transcription. This setup enabled us to identify intrinsic properties, originating from muscle precursor cells and retained in the corresponding myocytes. Bioinformatic and statistical methods, including differential expression analysis, gene-set analysis, and metabolic network analysis, were used to characterize the different myocytes. Results: We found that the transcriptional program associated with obesity alone was strikingly similar to that induced specifically by T2D. We identified a candidate epigenetic mechanism, H3K27me3 histone methylation, mediating these transcriptional signatures. T2D and obesity were independently associated with dysregulated myogenesis, down-regulated muscle function, and up-regulation of inflammation and extracellular matrix components. Metabolic network analysis identified that in T2D but not obesity a specific metabolite subnetwork involved in sphingolipid metabolism was transcriptionally regulated. Conclusions: Our findings identify inherent characteristics in myocytes, as a memory of the in vivo phenotype, without the influence from a diabetic or obese extracellular environment, highlighting their importance in the development of T2D.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD , 2017. Vol. 9, 47
Keyword [en]
Type 2 diabetes, Obesity, Skeletal myocytes, RNA-seq, Gene expression, Gene-set analysis, Metabolic network
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:kth:diva-208721DOI: 10.1186/s13073-017-0432-2ISI: 000401957400001PubMedID: 28545587Scopus ID: 2-s2.0-85019583608OAI: oai:DiVA.org:kth-208721DiVA: diva2:1108069
Note

QC 2017-06-12

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

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Nielsen, Jens

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Gene TechnologyScience for Life Laboratory, SciLifeLab
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