TY - JOUR

T1 - Type 2 diabetes and obesity induce similar transcriptional reprogramming in human myocytes

AU - Väremo, Leif

AU - Henriksen, Tora Ida

AU - Scheele, Camilla

AU - Broholm, Christa

AU - Pedersen, Maria

AU - Uhlén, Mathias

AU - Pedersen, Bente Klarlund

AU - Nielsen, Jens

PY - 2017/5/25

Y1 - 2017/5/25

N2 - 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.

AB - 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.

KW - Adult

KW - Computational Biology

KW - Diabetes Mellitus, Type 2

KW - Epigenesis, Genetic

KW - Female

KW - Histones

KW - Humans

KW - Inflammation

KW - Male

KW - Methylation

KW - Middle Aged

KW - Muscle Development

KW - Muscle Fibers, Skeletal

KW - Obesity

KW - Sequence Analysis, RNA

KW - Sphingolipids

KW - Journal Article

U2 - 10.1186/s13073-017-0432-2

DO - 10.1186/s13073-017-0432-2

M3 - Journal article

C2 - 28545587

VL - 9

JO - Genome Medicine

JF - Genome Medicine

SN - 1756-994X

M1 - 47

ER -