The Multiple Roles of Lactate in the Skeletal Muscle

Abstract

Believed for a long time to be merely a waste product of cell metabolism, lactate is now considered a molecule with several roles, having metabolic and signalling functions together with a new, recently discovered role as an epigenetic modulator. Lactate produced by the skeletal muscle during physical exercise is conducted to the liver, which uses the metabolite as a gluconeogenic precursor, thus generating the well-known "Cori cycle". Moreover, the presence of lactate in the mitochondria associated with the lactate oxidation complex has become increasingly clear over the years. The signalling role of lactate occurs through binding with the GPR81 receptor, which triggers the typical signalling cascade of the G-protein-coupled receptors. Recently, it has been demonstrated that lactate regulates chromatin state and gene transcription by binding to histones. This review aims to describe the different roles of lactate in skeletal muscle, in both healthy and pathological conditions, and to highlight how lactate can influence muscle regeneration by acting directly on satellite cells.

Keywords: GPR81 receptor; lactate; muscle renewal.

Figure 1

The route of lactate in the skeletal muscle. Glucose (which enters in the muscle through the GLUT4 transporter) is oxidised in two molecules of pyruvate during glycolysis. In anaerobic and in energy-demand conditions, lactate dehydrogenase (LDH) transforms pyruvate into lactate (as shown in the rectangle). Lactate can shuttle between the cytoplasm and the extracellular environment through the two transporters, MCT4 (out of the cell) and MCT1 (within the cell). Extracellular lactate can bind to the specific receptor GPR81. Ligand binding leads to the activation of inhibitory G proteins and the decreased production of cyclic AMP (cAMP). In turn, Protein Kinase A (PKA) activity and phosphorylation of CREB transcription factor are reduced, thus leading to decreased lipolysis. The figure was created with biorender.com.

Figure 2

The lactate in the mitochondria. Lactate produced in the cytoplasm by cytoplasmic LDH (cLDH) enters the intermembrane space, freely crossing the outer mitochondrial membrane. Here, the mitochondrial LDH (mLDH) transforms lactate in pyruvate, which enters the mitochondrial matrix through the MCT1 transporter. MCT1, localised in the inner mitochondrial membrane, together with cytochrome oxidase (COX) and mLDH constitute the so-called “lactate mitochondrial oxidation complex”. Cytoplasmic pyruvate directly enters the mitochondrial matrix, passing through the mitochondrial pyruvate complex (MCP) located in the inner mitochondrial membrane. In the mitochondrial matrix, pyruvate becomes the substrate of the pyruvate dehydrogenase complex that catalyses the conversion of the pyruvate into acetyl CoA. The figure was created with biorender.com.