Signals from the Circle: Tricarboxylic Acid Cycle Intermediates as Myometabokines

Abstract

Regular physical activity is an effective strategy to prevent and ameliorate aging-associated diseases. In particular, training increases muscle performance and improves whole-body metabolism. Since exercise affects the whole organism, it has countless health benefits. The systemic effects of exercise can, in part, be explained by communication between the contracting skeletal muscle and other organs and cell types. While small proteins and peptides known as myokines are the most prominent candidates to mediate this tissue cross-talk, recent investigations have paid increasing attention to metabolites. The purpose of this review is to highlight the potential role of tricarboxylic acid (TCA) metabolites as humoral mediators of exercise adaptation processes. We focus on TCA metabolites that are released from human skeletal muscle in response to exercise and provide an overview of their potential auto-, para- or endocrine health-promoting effects.

Keywords: TCA cycle; arterio-venous difference; citrate; exercise; exercise adaptation; liver; myometabokine; succinate.

Figure 1

The concept of myometabokines. Metabolites released from the contracting skeletal muscle can regulate transcription and translation, enzyme activities and signaling cascades by binding to receptors or after transporter-mediated cellular uptake. By initiating these events in the skeletal muscle or in other tissues, adaptive responses to physical activity are supported. The figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com (accessed on 22 June 2021).

Figure 2

Exercise-induced changes in TCA intermediate concentrations and fluxes. Intramuscular and plasma concentrations of most TCA intermediates increase above resting levels in the contracting skeletal muscle [23,27]. There is evidence of an increased muscular release of citrate [35,36], succinate [37,38], fumarate [38] and malate [38,39], as shown by analyses of arterio-venous differences. Citrate, succinate and malate are taken up into the hepato-splanchnic region, suggesting an uptake by the liver [36,39]. The figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com (accessed on 22 June 2021).

Figure 3

Action of succinate as a myometabokine. Skeletal muscle releases succinate during exercise, resulting in elevated plasma levels. Succinate then mediates signaling on target organs by either binding to its specific cell surface receptor SUCNR1 or after cellular uptake via SLC13A3. Solid arrows: succinate-mediated effect in exercise adaptation has been shown; dashed arrows: signaling function not studied in the context of exercise to date. The figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com (accessed on 22 June 2021).