Control of Muscle Metabolism by the Mediator Complex

Abstract

Exercise represents an energetic challenge to whole-body homeostasis. In skeletal muscle, exercise activates a variety of signaling pathways that culminate in the nucleus to regulate genes involved in metabolism and contractility; however, much remains to be learned about the transcriptional effectors of exercise. Mediator is a multiprotein complex that links signal-dependent transcription factors and other transcriptional regulators with the basal transcriptional machinery, thereby serving as a transcriptional "hub." In this article, we discuss recent studies highlighting the role of Mediator subunits in metabolic regulation and glucose metabolism, as well as exercise responsiveness. Elucidation of the roles of Mediator subunits in metabolic control has revealed new mechanisms and molecular targets for the modulation of metabolism and metabolic disorders.

Figure 1.

Mediator complex transcriptional hub. The Mediator complex regulates transcription by interacting with nuclear receptors, transcription factors (TFs), RNA polymerase II (Pol II), and enhancers.

Figure 2.

Mediator complex composition. The Mediator complex consists of the head (gray), middle (blue), and tail (green) domains. The kinase submodule (yellow) reversibly associates with the core complex and regulates Mediator transcriptional activity.

Figure 3.

Mediator complex subunits involved in regulation of metabolic processes (highlighted in red).

Figure 4.

Regulatory sequences in the Glut4 promoter and the factors that bind to them in skeletal muscle. Exercise increases the binding of GLUT4 enhancer factor (GEF) and an MEF2A/D heterodimer to the indicated binding domains in the Glut4 promoter. Krüppel-like factor (KLF)-15, MyoD, NURR1, and thyroid hormone receptor (TR)α1 also bind the Glut4 promoter. NRE, NURR1 response element; TRE, thyroid hormone response element.

Figure 5.

Schematic of the major signaling pathways involved transmitting of exercise effect on glucose metabolism. AMPK, AMP-activated protein kinase; HDAC, histone deacetylase; MAPK, mitogen-activated protein kinase; PGC-1, peroxisome proliferator-activated receptor coactivator 1.