Lactate as a signaling molecule : A potential role in controlling exercise induced adaptations in human skeletal muscle

Abstract: Introduction The lactate molecule has a key role in human energy metabolism, particularly in skeletal muscle: acting as a buffer within the muscle cell enabling glycolysis to continue during high energy demand, as well as acting as an energy shuttle between cells. The lactate molecule has also lately been shown to act as a signaling molecule in non-human models acting as a signaling molecule regulating the transcriptional process, potentially controlling the expression of several important metabolic proteins. To date, this notion lacks experimental support in human skeletal muscle. This study therefore aimed to explore the potential function of lactate as a signaling molecule in human skeletal muscle. Method This study used samples obtained from a randomized cross-over intervention where subjects (n=16) were infused with either lactate or saline during resistance exercise using the legs. Muscle biopsies that had been obtained at rest, 90- and 180-min post exercise were used to quantify the gene expression of monocarboxylate transporter (MCT) 1 & 4, Vascular Endothelial Growth Factor (VEGF), lactate dehydrogenase (LDH), G protein-coupled receptor 81 (GPR81), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) total, isoform 1 and isoform 4, as well as mitochondrial uncoupling protein 3 (UCP3). Protein expression of LDH, GPR81, MCT1 as well as total and phosphorylated levels of cAMP Response Element-Binding Protein (CREB) was assessed in samples taken at rest, post-exercise as well as 90- and 180-min of recovery. Results The lactate infusion did not alter any response in any of the proteins and genes investigated, but there was an effect of exercise on the expression several genes. PGC1-α total, isoform 1 and isoform 4 expression were increased due to exercise in both trials, approximately 9-fold, 2-fold and 10-fold respectively compared to baseline. VEGF gene expression increased 2-fold compared to baseline. The expression GPR81, UCP3, LDH, GPR81, MCT 1 and MCT 4 did not have any effects of either exercise or differed between infusions. No levels of total protein was affected, but there was a significant lowering of phosphorylated CREB at ser133 following exercise but not affected by the infusion. Conclusions The lack of effect could be attributed to either insufficient circulatory lactate levels needed for stimulation of the postulated effects, that the muscle contractions are not potent enough to override potential influence by lactate, or that the lactate molecule lacks signaling properties in human skeletal muscle in the explored pathway.