A Multivariate Screening Strategy for Investigating Metabolic Effects of Strenuous Physical Exercise in Human Serum

Pohjanen, Elin; Thysell, Elin; Jonsson, Pär; Eklund, Caroline; Silfver, Anders; Carlsson, Inga-Britt; Lundgren, Krister; Moritz, Thomas; Svensson, Michael; Antti, Henrik

doi:10.1021/pr070007g

Cited by 104 publications

(96 citation statements)

References 37 publications

(48 reference statements)

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“…Although many studies have assessed the effect of strenuous exercise on the metabolite profile in blood, none identified the N-lactoyl-amino acids (44)(45)(46). Nevertheless, many of the studies report multiple unidentified exercise-dependent metabolites, most likely including N-lactoyl-amino acids.…”

Section: Discussionmentioning

confidence: 99%

N -lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids

Jansen

Addie

Merkx³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Despite technological advances in metabolomics, large parts of the human metabolome are still unexplored. In an untargeted metabolomics screen aiming to identify substrates of the orphan transporter ATP-binding cassette subfamily C member 5 (ABCC5), we identified a class of mammalian metabolites, N-lactoyl-amino acids. Using parallel protein fractionation in conjunction with shotgun proteomics on fractions containing N-lactoyl-Phe-forming activity, we unexpectedly found that a protease, cytosolic nonspecific dipeptidase 2 (CNDP2), catalyzes their formation. N-lactoyl-amino acids are ubiquitous pseudodipeptides of lactic acid and amino acids that are rapidly formed by reverse proteolysis, a process previously considered to be negligible in vivo. The plasma levels of these metabolites strongly correlate with plasma levels of lactate and amino acid, as shown by increased levels after physical exercise and in patients with phenylketonuria who suffer from elevated Phe levels. Our approach to identify unknown metabolites and their biosynthesis has general applicability in the further exploration of the human metabolome.unknown metabolites | untargeted metabolomics | ABCC5 | MRP5 | physical exercise U ntargeted metabolomics aims to provide a comprehensive snapshot of the metabolome and is becoming a mainstream technique to discover biomarkers, to study the effects of interventions, and to discover the function of enzymes (1).Recent technical improvements now make it possible to detect several thousand metabolites in a single untargeted metabolomics analysis, but the identity of these metabolites is initially not known beyond their molecular mass (1). Knowing the chemical identity of metabolites is crucial for the proper interpretation of metabolomic studies, however. Online metabolite databases like METLIN (∼240,000 entries) and the Human Metabolome Database (HMDB; ∼42,000 entries) contain vast numbers of metabolites and are extremely useful to annotate the detected molecular masses (2, 3). These databases cover large parts of the metabolome, but significant gaps remain. Due to poorly characterized and promiscuous enzymes, the human metabolome is much larger than initially anticipated (4). State-of-the-art untargeted metabolomics studies still report up to 40% unidentified, but potentially important, metabolites that can be detected reproducibly (5-8). Nevertheless, unknown metabolites are only rarely characterized because of the extensive work required for de novo structure elucidation (9-11). Here, we describe the characterization of a class of mammalian metabolites that we discovered in an untargeted metabolomic screen aimed to identify substrates of the orphan transporter ATP-binding cassette subfamily C member 5 (ABCC5).ABCC5 is a member of the C-branch of the superfamily of ABC transporters, which use the energy provided by the hydrolysis of ATP to transport substrates across the plasma membrane (12). ABCC5, also known as multidrug resistance-associated protein 5 (MRP5), is ubiquitously expressed, but levels in b...

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Section: Discussionmentioning

confidence: 99%

N -lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids

Jansen

Addie

Merkx³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…A wide range of metabolites present in plasma and serum has been determined using liquid chromatography mass spectrometry and/or gas-chromatography mass spectrometry collected pre-and post-exercise. In most cases, a wide range of metabolites have been reported (Pohjanen et al 2007, Lewis et al 2010, Peake et al 2014 to exist and that with exercise changes in metabolites related to carbohydrate, triglyceride and markers of the tricarboxylic acid have been reported. Peake et al (2014), these studies were not hypothesis driven and are more observational in nature.…”

Section: Figurementioning

confidence: 99%

Metabolic and endocrine response to exercise: sympathoadrenal integration with skeletal muscle

Ball¹

2014

Journal of Endocrinology

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Skeletal muscle has the capacity to increase energy turnover by w1000 times its resting rate when contracting at the maximum force/power output. Since ATP is not stored in any appreciable quantity, the muscle requires a coordinated metabolic response to maintain an adequate supply of ATP to sustain contractile activity. The integration of intracellular metabolic pathways is dependent upon the cross-bridge cycling rate of myosin and actin, substrate availability and the accumulation of metabolic byproducts, all of which can influence the maintenance of contractile activity or result in the onset of fatigue. In addition, the mobilisation of extracellular substrates is dependent upon the integration of both the autonomic nervous system and endocrine systems to coordinate an increase in both carbohydrate and fat availability. The current review examines the evidence for skeletal muscle to generate power over short and long durations and discusses the metabolic response to sustain these processes. The review also considers the endocrine response from the perspective of the sympathoadrenal system to integrate extracellular substrate availability with the increased energy demands made by contracting skeletal muscle. Finally, the review briefly discusses the evidence that muscle acts in an endocrine manner during exercise and what role this might play in mobilising extracellular substrates to augment the effects of the sympathoadrenal system.

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“…Results can be prioritized based on cross-validation, and only those that meet a preset threshold of predictive ability are considered potential 'true positives.' Crossvalidation methods have been widely used over the last decade in genomic, 41,42 metabolomic, 43 proteomic, 44,45 and transcriptomic 46 -48 studies as a method for discriminating between true associations and false-positive associations.…”

Section: Statisticsmentioning

confidence: 99%

The genetic architecture of fasting plasma triglyceride response to fenofibrate treatment

et al. 2008

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Metabolic response to the triglyceride (TG)-lowering drug, fenofibrate, is shaped by interactions between genetic and environmental factors, yet knowledge regarding the genetic determinants of this response is primarily limited to single-gene effects. Since very low-density lipoprotein (VLDL) is the central carrier of fasting TG, identifying factors that affect both total TG and VLDL -TG response to fenofibrate is critical for predicting individual fenofibrate response. As part of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, 688 individuals from 161 families were genotyped for 91 single-nucleotide polymorphisms (SNPs) in 25 genes known to be involved in lipoprotein metabolism. Using generalized estimating equations to control for family structure, we performed linear modeling to investigate whether single SNPs, single covariates, SNP -SNP interactions, and/or SNP -covariate interactions had a significant association with the change in total fasting TG and fasting VLDL -TG after 3 weeks of fenofibrate treatment. A 10-iteration fourfold cross-validation procedure was used to validate significant associations and quantify their predictive abilities. More than one-third of the significant, cross-validated SNP -SNP interactions predicting each outcome involved just five SNPs, showing that these SNPs are of key importance to fenofibrate response. Multiple variable models constructed using the top-ranked SNPcovariate interactions explained 11.9% more variation in the change in TG and 7.8% more variation in the change in VLDL than baseline TG alone. These results yield insight into the complex biology of fenofibrate response, which can be used to target fenofibrate therapy to individuals who are most likely to benefit from the drug.

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A Multivariate Screening Strategy for Investigating Metabolic Effects of Strenuous Physical Exercise in Human Serum

Cited by 104 publications

References 37 publications

N -lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids

N -lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids

Metabolic and endocrine response to exercise: sympathoadrenal integration with skeletal muscle

The genetic architecture of fasting plasma triglyceride response to fenofibrate treatment

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