Utilization of lactic acid in human myotubes and interplay with glucose and fatty acid metabolism

Jenny Lund,Ragna H Tingstad,Nataša Nikolić,Alfons Van Hees,Vigdis Aas

doi:10.1038/s41598-018-28249-5

Jenny Lund, Ragna H Tingstad + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-28249-5

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Abstract

Once assumed only to be a waste product of anaerobe glycolytic activity, lactate is now recognized as an energy source in skeletal muscles. While lactate metabolism has been extensively studied in vivo, underlying cellular processes are poorly described. This study aimed to examine lactate metabolism in cultured human myotubes and to investigate effects of lactate exposure on metabolism of oleic acid and glucose. Lactic acid, fatty acid and glucose metabolism were studied in myotubes using [14C(U)]lactic acid, [14C]oleic acid and [14C(U)]glucose, respectively. Myotubes expressed both the MCT1, MCT2, MCT3 and MCT4 lactate transporters, and lactic acid was found to be a substrate for both glycogen synthesis and lipid storage. Pyruvate and palmitic acid inhibited lactic acid oxidation, whilst glucose and α-cyano-4-hydroxycinnamic acid inhibited lactic acid uptake. Acute addition of lactic acid inhibited glucose and oleic acid oxidation, whereas oleic acid uptake was increased. Pretreatment with lactic acid for 24 h did not affect glucose or oleic acid metabolism. By replacing glucose with lactic acid during the whole culturing period, glucose uptake and oxidation were increased by 2.8-fold and 3-fold, respectively, and oleic acid oxidation was increased 1.4-fold. Thus, lactic acid has an important role in energy metabolism of human myotubes.

Highlights

Lactate is produced from glucose through glycolysis and the conversion of pyruvate by lactate dehydrogenase (LDH)
MCT2 and MCT3, were studied at protein level (Fig. 1b,c). mRNA expression level of MCT4 (SLC16A4) was reduced in cells treated with 4 mM lactic acid (Fig. 1a), while protein levels of other monocarboxylate transporters (MCTs) were unaffected after 24 h of lactic acid pretreatment, except for MCT2, which was reduced in cells treated with 10 mM lactic acid (Fig. 1b,c)
The aim of the present study was to explore the ability of cultured human myotubes to utilize lactate as a fuel source, and to investigate effects of lactate on the metabolism of the two other main energy substrates, glucose and oleic acid

Summary

Introduction

Lactate is produced from glucose through glycolysis and the conversion of pyruvate by lactate dehydrogenase (LDH). Energy required for cellular functions, including contraction, is provided by ATP hydrolysis to ADP and Pi. There are three main mechanisms to generate ATP in skeletal muscle; creatine kinase activity, glycolysis and mitochondrial oxidative phosphorylation. A well-described effect of endurance exercise in skeletal muscles is increased mitochondrial content, which serves as a larger sink for pyruvate. Of importance is the upregulation of muscle MCT1 expression by exercise and MCT4 expression by hypoxia, implying important role of the latter transporter in cells relying on anaerobic glycolysis for energy production[16]. Energy substrate preference in skeletal muscle is variable, and during the fed state, increased availability of plasma glucose stimulates glucose oxidation and fatty acid synthesis, whereas fatty acid oxidation increases both during fasting and sustained exercise[26,27]. Role of lactate in metabolic switching of skeletal muscle cells has, to our knowledge, not been described

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