Editors' ChoiceMetabolism

Improved glucose metabolism without skeletal muscle MED13

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Science Signaling  01 Mar 2016:
Vol. 9, Issue 417, pp. ec44
DOI: 10.1126/scisignal.aaf5516

Understanding the mechanisms that control glucose uptake and metabolism in skeletal muscle can aid in developing strategies to improve organismal metabolism and reduce insulin resistance. Amoasii et al. knocked out MED13, a specific subunit of the Mediator complex, in mouse skeletal muscle and analyzed metabolism of these animals on a high-fat diet. The Mediator complex links transcription factors to the core transcriptional machinery. Compared with control mice, the MED13 muscle-specific knockout (MED13-mKO) mice had improved glucose tolerance and insulin sensitivity and reduced fatty liver (hepatic steatosis). However, the MED13-mKO mice gained just as much weight as the control mice when fed the high-fat diet. Insulin-stimulated glucose uptake and glycogen synthesis was selectively increased in the skeletal muscles of the MED13-mKO mice fed the high-fat diet. Gene expression profiling of RNAseq data indicated that carbohydrate metabolism and small molecule transport pathways were increased in the muscles of the MED13-mKO mice. These data also indicated that MED13 suppressed the expression of Nurr1, which encodes a transcription factor that regulates genes involved in metabolism. The muscles of the MED13-mKO had increased abundance of the glucose uptake transporter GLUT4, and the Glut4 gene had response elements for NURR1 and MEF2 that were adjacent to each other. Chromatin immunoprecipitation experiments showed that both proteins were present on the promoter and that occupancy was increased in the MED13-mKO muscles relative to that in control muscles from mice fed a high-fat diet. Coimmunoprecipitation experiments with transfected tagged proteins indicated that the proteins interacted, and reporter analysis with the Glut4 promoter revealed synergistic induction of the reporter when both NURR1 and MEF2 were present. Furthermore, the presence of MED13 blocked NURR1- and MEF2-induced reporter expression. Thus, the data indicated that MED13 inhibits expression of Nurr1 and may impede NURR1 and MEF2 from inducing gene expression, thereby limiting glucose uptake and glycogen storage in skeletal muscle. This metabolism-suppressing role of MED13 in skeletal muscle is opposite its metabolism-enhancing role in heart, liver, and adipose tissues. Thus, any therapeutic targeting of this molecule to enhance metabolism would have to selectively target skeletal muscle.

L. Amoasii, W. Holland, E. Sanchez-Ortiz, K. K. Baskin, M. Pearson, S. C. Burgess, B. R. Nelson, R. Bassel-Duby, E. N. Olson, A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism. Genes Dev. 30, 434–446 (2016). [PubMed]