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.

NURR1 activation in skeletal muscle controls systemic energy homeostasis

“…Key among the signal transducers in these pathways are AMPK and several calcium-sensitive kinases that regulate transcription by targeting class II histone deacetylases (HDACs), which relieves their repressive influence on MEF2 and other transcription factors (13-16). Integration of metabolic gene regulation also occurs through regulatory interactions between MEF2 and the nuclear coactivator PGC-1, which associates with PPAR and other nuclear receptors to enhance metabolic gene expression (17).Recently, we showed that MED13, a component of the Mediator complex, modulates systemic metabolism in skeletal muscle by suppressing the expression of Glut4 and other genes involved in glucose uptake and glycogen storage (18,19). Among a collection of genes up-regulated in skeletal muscle of MED13 mutant mice was the orphan nuclear receptor Nr4a2/Nurr1.…”

“…Recently, we showed that MED13, a component of the Mediator complex, modulates systemic metabolism in skeletal muscle by suppressing the expression of Glut4 and other genes involved in glucose uptake and glycogen storage (18,19). Among a collection of genes up-regulated in skeletal muscle of MED13 mutant mice was the orphan nuclear receptor Nr4a2/Nurr1.…”

Potential roles of mediator Complex Subunit 13 in Cardiac Diseases

“…In addition, RNA sequencing data reveals that gene expressions of nuclear receptor NURR1, salt-inducible kinase 1 (which activates the TF MEF2), and glucose transporter type 4 (GLUT4) are upregulated in MED13-mKO muscle. Muscle-specific MED13 primarily represses the MEF2/NURR1 cooperative pathway, thereby suppressing expression of glucose handling genes, such as GLUT4 [89][90][91]. The opposite functions of MED13 in the heart and muscle in systemic energy metabolism suggest tissue-specific functions for MED13 via various signaling pathways.…”

Whole-Transcriptome Analysis of Yak and Cattle Heart Tissues Reveals Regulatory Pathways Associated With High-Altitude Adaptation

“…"KEGG" is short for "Kyoto Encyclopedia of Genes and Genomes." (Knerr et al, 2005), oxidative phosphorylation, B/T cell receptor, natural killer cell-mediated cytotoxicity (Vaupel and Multhoff, 2018), and cardiac muscle contraction (Amoasii et al, 2018) signaling pathways were enriched, which are related to hypoxic adaptation systems and are important for oxygen transportation, environmental sensing, energy metabolism, and infection and immune defense systems. There were 15 genes associated with the above mentioned pathways, including cytochrome c oxidase subunit 7C (COX7C), mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3), BCL2 associated agonist of cell death (BAD), vav guanine nucleotide exchange factor 1 (VAV1), nuclear factor of activated T cells 2 (NFATC2), nuclear factor of activated T cells 1 (NFATC1), and phosphoinositide-3-kinase regulatory subunit 5 (PIK3R5), and these genes were significantly up-regulated (>10-fold) in the heart tissues of HAC and LWQY compared to LAC.…”