Muscle as a "mediator" of systemic metabolism

Abstract

Skeletal and cardiac muscles play key roles in the regulation of systemic energy homeostasis and display remarkable plasticity in their metabolic responses to caloric availability and physical activity. In this Perspective we discuss recent studies highlighting transcriptional mechanisms that govern systemic metabolism by striated muscles. We focus on the participation of the Mediator complex in this process, and suggest that tissue-specific regulation of Mediator subunits impacts metabolic homeostasis.

Figure 1. The Role of Muscle Fiber Types in the Regulation of Systemic Metabolism

(A) Slow-twitch myofibers have a high oxidative capacity and prefer fatty acids as substrate for ATP production. Fast-twitch fibers have a lower oxidative capacity and prefer glucose. Muscle fiber type can be altered by external and internal factors. Exercise increases the number of slow-twitch fibers, thus enhancing fatty acid utilization, while obesity increases fast-twitch fibers and causes slow-twitch fibers to become insulin resistant. Muscle fiber type is transcriptionally regulated, ultimately impacting systemic metabolism. (B) Nuclear receptors, such as PPARs, ERRs, TRs, and Nur77 activate transcription of genes involved in myofiber switching. PGC1α is a coregulator and acts with PPAR, ERR, and TR to drive the switch from fast to slow fibers. RIP140 and NCoR1 are corepresors for PPARs, ERRs, and TRs. TZDs, insulin sensitizing drugs, reactivate PPAR in the setting of diabetes and obesity, which can also lead to myofiber switching. PPAR, peroxisome proliferator-activated receptor; ERR, estrogen-related receptor; TR, thyroid hormone receptor; Nur77, orphan nuclear receptor NR4A1; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; RIP140, corepressor receptor-interacting protein 140; NCoR, nuclear receptor corepressor; TZD, thiazolidinediones.

Figure 2. The Mediator Complex

The transcriptionally active core Mediator complex consists of the head (blue), body (red), and tail (light green) domains, and the relative location of the subunits is depicted. The CDK8 kinase submodule (yellow) reversibly associates with the core complex and regulates Mediator transcriptional activity. The Mediator complex regulates transcription by interacting with nuclear receptors, general transcription factors (GTFs), RNA polymerase II (Pol II), and enhancers. TR, thyroid hormone receptor; PPARs, peroxisome proliferatoractivated receptors.

Figure 3. Mediator Subunits Alter Systemic Metabolism in a Muscle-Specific Manner

Perturbations of MED13 and MED30 in the heart alter metabolism. Overexpression of MED13 in the heart causes leanness, and loss of MED13 in the heart increases susceptibility of obesity and diabetes. Loss-of-function mutations in MED30 lead to altered substrate availability, heart failure, and death. Loss of MED1 in muscle causes a fast-to-slow muscle fiber type switch, which enhances insulin sensitivity and protects against obesity.

Figure 4. Proposed Roles for Mediator in Regulating Secreted Factors and Systemic Metabolism

Secreted factors released from adipose tissue and liver regulate skeletal and cardiac muscle metabolism, and many factors are released from heart and muscle that exert feedback on these tissues. While the role of Mediator in regulating secreted factors has not yet been investigated, it is highly likely that Mediator is involved in this process. See text for discussion.