Beyond newborn screening –
What can acylcarnitines tell us about health and disease?
December 1st, 2020 | 16:00 CET (10:00 EST)
Plasma concentrations of long-chain acylcarnitines and intracellular energy metabolism: How to find a black cat in a dark room?
Edgars Liepinsh, Ph.D.
Laboratory of Pharmaceutical Pharmacology
Latvian Institute of Org. Synthesis, Riga, Latvia
Mark Haid, Ph.D.
Head of Lipidomics Platform
Genome analysis center
Helmholtz Zentrum Munich, Germany
Quantitative acylcarnitine analysis with new biocrates technology
Therese Koal, Ph.D.
Chief Technology Officer
biocrates life sciences ag
The measurements of acylcarnitine concentrations are often included in the metabolomic assays, but obtained results are not always easy to interpret. In the past 10 years, long-chain acylcarnitine levels have emerged as markers of insulin resistance and diabetes; however, in most studies, they have been measured in fasted subjects, which is not an appropriate metabolic state for the characterization of insulin resistance. The fasted and postprandial states are characterized by different intensities of fatty acid (FA) metabolism and different prevailing regulatory mechanisms. Therefore, measurements of acylcarnitine levels in both states would help us to better understand the importance of changes in acylcarnitine concentrations in the context of metabolic status and the levels of other diagnostic markers.
Carnitine palmitoyltransferase 1 (CPT 1)-mediated long-chain acylcarnitine synthesis is a step in mitochondrial FA oxidation, and various mitochondrial disorders that are characterized by incomplete FA oxidation cause the accumulation of long-chain acylcarnitines. For those disorders, acylcarnitine measurements in the fasted state are appropriate for the assessment of mitochondrial function, while insulin resistance can be detected only in the postprandial state after a controlled glucose load. In a recent study, we tested whether a decrease in circulating long-chain acylcarnitine concentrations after glucose administration in a glucose tolerance test is associated with insulin sensitivity and can be used for the diagnosis of insulin resistance. We found that in contrary to short-chain and medium-chain acylcarnitines, the measurements of changes in plasma long-chain acylcarnitine concentrations after glucose load in fasted subjects are useful as diagnostic markers for muscle-specific insulin resistance.
Decrease of long-chain acylcarnitine synthesis has been confirmed as a promising approach in various disease models including myocardial infarction, atherosclerosis, and insulin resistance. Meldonium is the only clinically used cardiometabolic drug, whose mechanism of action is based on decreased long-chain acylcarnitine concentrations. In recent studies, pharmacological decrease of long-chain acylcarnitines is studied in models of inherited disorders, cancer, endotoxemia- and pulmonary hypertrophy-induced cardiac damage opening new horizons for long-chain acylcarnitine-lowering and mitochondria-protective strategies.
Running is at the forefront of self-training and individual health, with levels ranging from recreational to competitive. Thus, marathon runners include both top athletes who train professionally in order to regularly compete and amateur runners who are more concerned with making it to the finish line once a year. Although both types of athletes generally follow rigorous and prolonged training prior to a race, their metabolic responses differ.
This study by Schader et al. focused on a small male cohort who took part in the Munich marathon. The participants were split into 3 groups (top, average, or low performance runners) based on their performance in the marathon and overall fitness level. The runners’ metabolic profiles were measured with targeted metabolomics in blood plasma at several time points during training, right after completing the marathon, and a few days later, to assess the metabolic toll their bodies went through. The results showed a set of metabolites and metabolism indicators (sums and ratios of metabolites) that discriminated between the different groups and identified some of the metabolic pathways that were still at work up to three days after the marathon.
Right after the run, the levels of acylcarnitines (AC, intermediates in the degradation of fatty acids in mitochondria) and three AC ratios were increased for all groups, showing common responses to intense exercise. However, large differences in amino acids and arginine-related metabolites and ratios were measured between the top runners and the low performance groups. These differences suggested an accumulation of fatty acids after the race and the degradation of proteins for energy production in the low performance runners. Thus, supporting the well-known advice to properly prepare before running a marathon.