Proteome- and Transcriptome-Driven Reconstruction of the Human Myocyte Metabolic Network and Its Use for Identification of Markers for Diabetes.

Graphical Abstract Highlights d Reconstruction of a comprehensive myocyte-specific genome-scale metabolic model d Meta-analysis of type 2 diabetes transcription in skeletal muscle from six studies d Transcriptional regulation of metabolism around pyruvate, BCAAs, and THF d Myocyte metabolic model identifies a metabolic signature of diabetes Correspondence nielsenj@chalmers.se In Brief Type 2 diabetes is associated with an altered metabolism in skeletal myocytes. To elucidate these metabolic changes at a systems level, Vä remo et al. reconstructed the myocyte metabolic network and integrated it with transcription data from six different studies, identifying a consistent metabolic signature of diabetic muscle. SUMMARY 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 eluci-dation 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. Tran-scriptional changes were mapped on the myocyte GEM, revealing extensive transcriptional regulation in T2D, particularly around pyruvate oxidation, branched-chain amino acid catabolism, and tetrahy-drofolate metabolism, connected through the down-regulated 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.

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