Abstract
IntroductionLactate is an important signaling molecule with autocrine, paracrine and endocrine properties involved in multiple biological processes including regulation of gene expression and metabolism. Levels of lactate are increased chronically in diseases associated with cardiometabolic disease such as heart failure, type 2 diabetes, and cancer. Using neonatal ventricular myocytes, we tested the hypothesis that chronic lactate exposure could decrease the activity of cardiac mitochondria that could lead to metabolic inflexibility in the heart and other tissues.MethodsNeonatal rat ventricular myocytes (NRVMs) were treated for 48 h with 5, 10, or 20 mM lactate and CPT I and II activities were tested using radiolabelled assays. The molecular species profile of the major mitochondrial phospholipid, cardiolipin, was determined using electrospray ionization mass spectrometry along with reactive oxygen species (ROS) levels measured by Amplex Red and mitochondrial oxygen consumption using the Seahorse analyzer.ResultsCPT I activity trended downward (p = 0.07) and CPT II activity significantly decreased with lactate exposure (p < 0.001). Cardiolipin molecular species containing four 18 carbon chains (72 carbons total) increased with lactate exposure, but species of other sizes decreased significantly. Furthermore, ROS production was strongly enhanced with lactate (p < 0.001) and mitochondrial ATP production and maximal respiration were both significantly down regulated with lactate exposure (p < 0.05 and p < 0.01 respectively).ConclusionsChronic lactate exposure in cardiomyocytes leads to a decrease in fatty acid transport, alterations of cardiolipin remodeling, increases in ROS production and decreases in mitochondrial oxygen consumption that could have implications for both metabolic health and flexibility. The possibility that both intra-, or extracellular lactate levels play roles in cardiometabolic disease, heart failure, and other forms of metabolic inflexibility needs to be assessed in vivo.
Highlights
Lactate is an important signaling molecule with autocrine, paracrine and endocrine properties involved in multiple biological processes including regulation of gene expression and metabolism
Such procedures result in upregulation of hundreds of genes associated with adaption to physical exercise including those of the Mitochondrial Lactate Oxidation Complex mitochondrial lactate oxidation complex (mLOC) [14]
We show that lactate exposure increases reactive oxidative species (ROS) which have been linked to mitochondrial damage and dysfunction [28, 29], and lastly, chronic lactate exposure downregulates mitochondrial oxygen coupling efficiency and consumption rate
Summary
Lactate is an important signaling molecule with autocrine, paracrine and endocrine properties involved in multiple biological processes including regulation of gene expression and metabolism. Despite observations that lactate is a favored over glucose as energy substrate at the whole body [1–5] and tissues levels in skeletal muscle [2, 3], heart [6–8] and brain [9], and that in isolated mitochondrial preparations lactate is readily oxidized [10–12], it has been observed that ROS production has been observed in myocytes incubated with prolonged high lactate levels [13] Such procedures result in upregulation of hundreds of genes associated with adaption to physical exercise including those of the Mitochondrial Lactate Oxidation Complex mLOC [14]. In aggregate such observations give rise to the idea that while acute, but intermittent lactate exposure as occurs in physical exercise is adaptive, prolonged cellular exposure to lactate, as occurs in chronic inflammatory diseases, may be maladaptive with regard to fatty acid oxidation, leading to metabolic reprograming and disease state. These observations underscore the important role of the cardiolipin molecular species profile in regulation of fatty acid oxidation
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