TYPE Review

PUBLISHED 15 January 2024

DOI 10.3389/fphys.2023.1332104

Research advances in the

OPEN ACCESS application of metabolomics in
EDITED BY
Simone Luti,
University of Florence, Italy
exercise science
REVIEWED BY
Liliana C. Baptista, Shuo Qi 1, Xun Li 1, Jinglun Yu 2* and Lijun Yin 3*
University of Alabama at Birmingham, 1
United States School of Sport and Health, Shandong Sport University, Jinan, China, 2School of Exercise and Health,
Samuel Honório, Shanghai University of Sport, Shanghai, China, 3School of Sport, Shenzhen University, Shenzhen, China
Polytechnic Institute of Castelo Branco,
Portugal
Bernardo A. Petriz,
University Centre of the Federal District, Brazil
Exercise training can lead to changes in the metabolic composition of an athlete’s
*CORRESPONDENCE
Jinglun Yu,
blood, the magnitude of which depends largely on the intensity and duration of
[email protected] exercise. A variety of behavioral, biochemical, hormonal, and immunological
Lijun Yin, biomarkers are commonly used to assess an athlete’s physical condition during
[email protected]
exercise training. However, traditional invasive muscle biopsy testing methods
RECEIVED 02 November 2023 are unable to comprehensively detect physiological differences and metabolic
ACCEPTED 27 December 2023
PUBLISHED 15 January 2024
changes in the body. Metabolomics technology is a high-throughput, highly
sensitive technique that provides a comprehensive assessment of changes in
CITATION
Qi S, Li X, Yu J and Yin L (2024), Research small molecule metabolites (molecular weight <1,500 Da) in the body. By
advances in the application of metabolomics in measuring the overall metabolic characteristics of biological samples, we can
exercise science. study the changes of endogenous metabolites in an organism or cell at a certain
Front. Physiol. 14:1332104.
doi: 10.3389/fphys.2023.1332104 moment in time, and investigate the interconnection and dynamic patterns
between metabolites and physiological changes, thus further understanding
COPYRIGHT
© 2024 Qi, Li, Yu and Yin. This is an open-access the interactions between genes and the environment, and providing
article distributed under the terms of the possibilities for biomarker discovery, precise training and nutritional
Creative Commons Attribution License (CC BY). programming of athletes. This paper summaries the progress of research on
The use, distribution or reproduction in other
forums is permitted, provided the original the application of exercise metabolomics in sports science, and looks forward to
author(s) and the copyright owner(s) are the future development of exercise metabolomics, with a view to providing new
credited and that the original publication in this approaches and perspectives for improving human performance, promoting
journal is cited, in accordance with accepted
academic practice. No use, distribution or exercise against chronic diseases, and advancing sports science research.
reproduction is permitted which does not
comply with these terms.
KEYWORDS

metabolomics, exercise, metabolism, nutrition, biomarkers

Introduction
A biomarker is a biological characteristic that can be measured and evaluated in an
organism or a biological sample, and can be used to indicate the physiological state of an
organism, disease risk, disease progression or treatment effect, and other information (Qiu
et al., 2023). Biomarkers can be molecules, cells, tissues, or physiological indicators, etc.
Common biomarkers include genes, proteins, metabolites, hormones, and cell surface
markers (Di Minno et al., 2022). Metabolomics is the quantitative analysis of small
molecular weight metabolites (molecular weight <1,500 Da) in organisms, such as
carbohydrates, amino acids, organic acids, nucleotides, and lipids, using mass
spectrometry or magnetic resonance spectroscopy, and by studying the pattern of
change of organisms or endogenous metabolites at a given moment (Kelly et al., 2020;
Schranner et al., 2020; Belhaj et al., 2021; Shimada et al., 2021; Khoramipour et al., 2022). It
is possible to investigate the interconnection and dynamic pattern of metabolites and
physiological and pathological changes (Kelly et al., 2020; Kistner et al., 2021).
Metabolomics reflects the genome, transcriptome, and proteome, as well as their

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FIGURE 1
Interconnections between metabolomics and the environment. Metabolomics reflects the genome, transcriptome, and proteome and their
interactions with the environment.

FIGURE 2
Workflow of exercise metabolomics studies. The workflow of exercise metabolomics research mainly includes problem formulation, study design,
sample collection, sample preparation, data collection, statistical analysis, and functional interpretation.

interactions with the environment, and provides an ideal way to measure become a powerful tool for studying metabolic processes, identifying
organismal phenotypes (Figure 1). Metabolomics data can provide useful potential biomarkers, and deciphering metabolic reprogramming in
insights into the biological effects of exercise, drug therapy, nutritional various diseases to reveal the underlying mechanisms of relevant
interventions, and more. Over the past decades, metabolomics has metabolic diseases (Belhaj et al., 2021).

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FIGURE 3
Comparison of metabolites between the long-term exercising population and the non-exercising population. The workflow of exercise
metabolomics research mainly includes problem formulation, study design, sample collection, sample preparation, data collection, statistical analysis,
and functional interpretation.

FIGURE 4
Metabolites, metabolic pathways of different exercise intensity category interventions.

Exercise can cause changes in the metabolism of many organs signal release, energy transfer, and intercellular communication in
and tissues of the body, both acute and prolonged exercise, causing the organism (Monnerat et al., 2020; Schranner et al., 2020; Belhaj
changes and adaptations in the body’s material metabolism and et al., 2021; Klein et al., 2021; Martins Conde et al., 2021). However,
energy metabolism. Meanwhile, metabolites also regulate cellular exercise physiology has traditionally only been able to study a small

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TABLE 1 Advantages and disadvantages of different chemical analysis methods.

Analytical platform Advantages Disadvantages

Nuclear magnetic resonance (NMR) Fast Analysis Low sensitivity

High resolution technology Small library of reference compounds

No derivatisation required More than one peak per metabolite

Simple preparation Limited to hydrophilic molecules

Highly reproducible Expensive instrumentation

Low cost

Structure can be determined

Fully automatable

Non-destructive methods

Gas chromatography–mass spectrometry (GC–MS) High sensitivity Lower yield

High resolution Requires chemical derivatisation

Large linear absorption range Not suitable for thermally unstable compounds

Suitable for volatile compounds High molecular weight

Large library of commercial and public reference spectra Only for compounds that can volatilise

Highly reproducible Complicated preparation process

Mostly automatable

Liquid chromatography–mass spectrometry (LC–MS) Usually no derivatisation required Low throughput

Can be used with a variety of separation methods Limited library of reference spectra

Multiple samples can be analyzed simultaneously Expensive instrumentation

Suitable for a wide range of compounds (polar and non-polar) Chromatographic separation required

Most sensitive metabolomics technology Advanced training required

Good automation capabilities Destructive methods

TABLE 2 Effects of different exercise durations on key metabolites.

Duration of different exercises Changes in key metabolites

Acute exercise of short duration Leucine, isoleucine, asparagine, methionine, lysine, glutamic acid, glutamine, alanine, dimethylguanidinovaleric acid and other
metabolites ↓

Long period of exercise Glucose, isoleucine, fatty acids, triglycerides, cholesterol, sphingolipids, lipoproteins and other metabolites ↓

number of genes, proteins, and metabolites and their responses or invasive testing methodology limits the motivation of subjects to
adaptations to exercise, with no more than 12 metabolites participate in the test and further limits the measurement of
measured using traditional methods and only one to two certain meaningful metabolic analyses, whereas the emergence
metabolic pathways at a time, failing to comprehensively detect of metabolomics has made it possible to conduct
exercise-induced physiological changes in tissues or metabolic comprehensive, high-throughput, minimally or non-invasive
pathways (Belhaj et al., 2021; Khoramipour et al., 2022). The metabolic studies in the field of exercise physiology (Castro
number of metabolites in the human body exceeds et al., 2020). This review briefly introduces the exercise
110,000 compounds and the number of metabolic signaling metabolomics technology and workflow, focuses on the research
pathways in the human body exceeds 40,000 (Wishart et al., progress of exercise metabolomics applied in the field of sports
2020). In addition, invasive muscle biopsies are required to science, and looks forward to the future development direction of
collect metabolic data in exercise physiology studies (Belhaj exercise metabolomics. The technique provides researchers with
et al., 2021; Tokarz et al., 2021). While invasive muscle biopsies an effective research tool, which helps to improve the practical
have successfully identified certain key metabolic pathways in the ability and depth of theoretical understanding of sports
body, such as glycolysis and β-oxidation of free fatty acids, this performance and chronic disease exercise control.

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Introduction to exercise metabolomics Sample collection and sample preparation

With the continuous development of histological techniques, In human metabolomics research, the most common sample
exercise physiology is increasingly using metabolomics to probe types are blood, urine, saliva, sweat, and fecal samples, with muscle
organismal phenotypes, reveal metabolic pathways through the biopsies and other types of tissue biopsies accounting for a lower
measurement of endogenous compounds, and identify percentage, and endogenous metabolites in the samples better reflect
biomarkers associated with exercise performance and fatigue, the physiological changes in the organism (Kelly et al., 2020;
which has been termed “exercise metabolomics” (Kelly et al., Khoramipour et al., 2022). Sample type, sample quantity, and
2020; Zhou et al., 2021). In 2007, Pohjanen et al. (2007) sample storage conditions are the keys to metabolomics
introduced exercise metabolomics to exercise science by experiments, each biological sample has advantages and
performing 90 min of stationary cycling on 24 healthy men, disadvantages, the most commonly used types of biological
collecting blood samples for gas chromatography-mass samples in exercise metabolomics research are blood and urine,
spectrometry (GC-MS) analysis, and identifying 420 metabolites, and the collection method is minimally invasive or non-invasive,
of which 34 were significantly altered, with an emphasis on the role and easy to be accepted by the subjects. Once collected, biological
of the most valuable biomarkers (glycerol and asparagine), which samples must be further processed or extracted to convert them into
demonstrated, for the first time, the potential of non-targeted GC- a state suitable for chemical analysis (Khoramipour et al., 2022).
MS metabolomics to provide a useful tool for the identification of
metabolic pathways associated with exercise performance and
fatigue. Metabolomics by mass spectrometry may provide a Chemical analysis platform and
comprehensive and unbiased approach to studying the metabolic data analysis
effects of exercise interventions (Pohjanen et al., 2007). Currently,
the most commonly used biological samples in exercise Chemical analysis platforms used for sample characterization in
metabolomics studies are blood and urine, and most studies use metabolomics research include Gas Chromatography-Mass
non-targeted metabolomics techniques, with mass spectrometry Spectrometry (GC-MS), Nuclear Magnetic Resonance (NMR),
being the most commonly used detection and analysis platform and Liquid Chromatography-Mass Spectrometry (LC-MS) (Table
in exercise metabolomics studies. 1) (Kelly et al., 2020; Nicolaides et al., 2021; Khoramipour et al.,
The main question in exercise science research is to understand 2022). The process of data processing and information analysis in
how exercise induces physiological adaptations in the body, such as metabolomics mainly includes the analysis of data, extraction of
an increase in muscle strength or aerobic metabolic capacity, and biological information, and functional interpretation of biological
how these adaptations affect health. But what are the molecular connotations (Khoramipour et al., 2022). The data generated in
network mechanisms and metabolic pathways that govern how metabolomics studies have multivariate characteristics, when the
humans adapt to exercise and gain health benefits (Sakaguchi number of metabolites in a given sample reaches hundreds or
et al., 2019; Blackburn et al., 2020; Febvey-Combes et al., 2021; thousands, multivariate analysis methods capable of dealing with
Babu et al., 2022)? These questions remain to be fully elucidated, and related variables are required to achieve reliable comparisons
the study of exercise metabolomics will greatly enrich the between multiple samples based on the whole set of variables.
understanding of these molecular network mechanisms and For example, Principal Components Analysis (PCA), Partial Least
metabolic pathways. Squares-Discriminant Analysis (PLS-DA), and Orthogonal Partial
Least Squares-Discriminant Analysis (OPLS-DA) (Castro et al.,
2020; Khoramipour et al., 2022).
Workflow of exercise metabolomics studies

As shown in Figure 2, the workflow of exercise metabolomics Advances in exercise

research includes 1) identifying the biological question of the metabolomics research
study; 2) developing a study design based on the biological
question of the study; 3) collecting experimental samples; 4) There is a multifactorial dosage relationship between the effects
preparing the samples; 5) analyzing the samples and acquiring of exercise on metabolic pathways, including the intensity of
the data using one or more analytical platforms; 6) statistically exercise, the duration of exercise, and the frequency of exercise
analyzing compounds based on the biological question and (Hargreaves and Spriet, 2020; Osawa et al., 2021). These factors can
experimental design to determine metabolic differences between strongly influence the metabolic changes in the organism after
different groups of samples; 7) researchers use software tools and exercise. In turn, the type and program of exercise, the level of
databases to integrate the detected compounds with the biological exercise, and even exercise nutrition can also affect the body’s
context to further enable metabolic pathway enrichment analysis, metabolism. In addition, the effect of exercise on the
metabolite mapping, and visualization, which can help inform metabolomics of chronic diseases is also a current research
future research questions and experimental designs (Belhaj et al., hotspot, which provides new perspectives on the prevention and
2021; Khoramipour et al., 2022). treatment of chronic diseases.

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Effects of different exercise durations on pathways, and high-intensity resistance training being dominated
body metabolism by anaerobic metabolic pathways, with an increase in glycolysis and
purine metabolism pathways (Figure 4). The effect of exercise
There are some differences in the categories of metabolites induced intensity on metabolic profiles was also present in outstanding
in the body by different modes of exercise. For example, a short period athletes, Al-Khelaifi et al. (2018) collected blood samples from
of acute exercise can immediately cause changes in the metabolic outstanding athletes in different sports and analyzed the changes
pathways of skeletal muscle substrate utilization, and the changes in in 743 metabolites based on an LC-MS platform, and found that
tricarboxylic acid (TCA) cycle metabolites are obvious after 1 h of outstanding athletes with low-intensity endurance training had
exercise (Kelly et al., 2020; Tabone et al., 2021). Amino acids such as higher levels of serum sex hormones (testosterone and
leucine, isoleucine, asparagine, methionine, lysine, glutamine, and progesterone), and lower levels of diacylglycerol and eicosanoids;
alanine decreased significantly after 14 h of exercise, reflecting the while high-intensity strength-trained elite athletes had higher levels
large magnitude of changes in amino acid levels after acute exercise of phospholipids and xanthines (Al-Khelaifi et al., 2018). Aerobic
(Sakaguchi et al., 2019). Changes in plasma fatty acids, ketone bodies, training mainly includes, running, cycling, football, and endurance
bile acids, and triglycerides also showed changes that can last for several sports such as swimming. Resistance training usually consists of
hours after acute exercise, eventually returning to pre-exercise levels high load, low repetition muscle contractions during a race
(Sakaguchi et al., 2019). For example, weight lifting and dumbbell (Granacher et al., 2016). Examples include weightlifting training,
training, resistance exercises such as pull-ups. Sakaguchi et al. found polymetric training, or machine-based training that includes upper
that within 24 h of a short period of acute exercise in the body, and lower body exercises such as squats, jumps, weighted sprints,
Significant changes in metabolites such as carbohydrates, TCA push-ups, and pull-ups (Fiorenza et al., 2019). This type of training
circulating metabolites, fatty acids, carnitine, ketone bodies, amino is known to promote metabolic changes that facilitate anaerobic
acids, and their derivatives were found (Sakaguchi et al., 2019). processes and increase muscle strength. Exercises such as
Nayor et al. (2022) found that dimethylguanidinopentanoic acid and gymnastics, martial arts and rock climbing also exhibit a high
glutamate levels were reduced after a short period of acute exercise resistance component. In addition, endurance and resistance
(Nayor et al., 2022). Therefore, short-duration acute exercise can cause components are often combined, for example, in exercise
more substantial changes in metabolites related to energy metabolism. interventions that combine running with weight training. Many
Kujala et al. (2013) compared amino acid levels in several groups of sports also have significant endurance and resistance components,
twins who had been exercising consistently for several decades and such as sprinting, boxing and rugby.
found that the fatty acid composition of the long-term exercising The type of sport also affects the body’s metabolic differences,
population gradually shifted from a saturated to an unsaturated state such as marathons, track, boxing, cycling, football, rowing, rugby
and that glucose and isoleucine levels were lower (Kujala et al., 2013). As swimming, etc. There are differences in metabolic changes in
shown in Figure 3, changes in metabolites such as glucose, fatty acids, different sports, and the reason for metabolic differences in
and triglycerides were observed in both long-term exercising and long- different sports is mainly due to the different proportion of the
term non-exercising populations, but higher levels of fatty acids, energy supply system, such as weightlifters with the phosphate
triglycerides and cholesterol existed in long-term non-exercising energy supply system, rowers with the glycolysis energy supply
populations, which are prone to chronic metabolic diseases such as system, and marathon athletes with the aerobic oxidative energy
dyslipidemia, hypertension, cardiovascular disease, stroke, type supply system (Al-Khelaifi et al., 2018). Even the metabolism of
2 diabetes and metabolic syndrome (Mendham et al., 2021; Remie athletes in different positions in the same sport varies, e.g., there are
et al., 2021; McClain et al., 2022). However, people who exercise for a metabolic differences between football goalkeepers and field players
long period can accelerate the utilization of energy substances, reduce participating in the same game, and these differences are likely to be
the accumulation of fat, and lower the levels of fatty acids, triglycerides, caused by exercise intensity and exercise duration (Blackburn et al.,
and cholesterol, which is conducive to the maintenance of healthy body 2020; Schader et al., 2020; Bester et al., 2021; Pugh et al., 2021). In
weight as well as lowering the risk of chronic diseases (Table 2) (Tzimou addition, athletes in endurance sports have significantly increased
et al., 2020; Bihlmeyer et al., 2021; Koay et al., 2021; Lemonakis et al., levels of glycolytic products, TCA cycle intermediates, nucleotide
2022). In the future, we will focus on the far-reaching effects of long- metabolites, acylcarnitines, and branched-chain amino acids, which
term exercise on weight loss and health. are frequently associated with aerobic metabolic pathways.
Resistance training studies have shown significant increases in
levels of creatine, choline, guanidine acetate, and hypoxanthine
Effects of different exercise intensities on and decrease in creatinine levels in athletes in strength and
body metabolism explosive events, metabolites that are commonly associated with
muscle growth, intracellular buffering, and methyl regulation
The most common metabolic pathways induced by exercise in (Khoramipour et al., 2022).
the body are changes in fatty acid metabolism, fat mobilization,
lipolysis, TCA cycle, glycolysis, amino acid metabolism, carnitine
metabolism, purine metabolism, and cholesterol metabolism (Kelly Effects of different levels of exercise on the
et al., 2020). Different exercise intensities have different effects on body’s metabolism
the body’s metabolism, with low-intensity aerobic training being
dominated by aerobic metabolic pathways, with increases in the The level of exercise also affects the body’s metabolic differences,
TCA cycle, fatty acid metabolism and amino acid metabolic and Enea et al. used metabolomics for the first time to differentiate

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between metabolite changes in trained and untrained women, who the modulatory effects of ginseng supplementation on the
underwent a 75% maximal oxygen uptake test, and then collected metabolic patterns of professional athletes and explored the
urine samples to analyze the metabolite changes based on an NMR mechanism of ginseng’s antifatigue effects. Their metabolite
platform, and found that the metabolites of creatine, lactic acid, analysis of blood samples from athletes based on a GC-MS
pyruvic acid, alanine, β-hydroxybutyric acid, acetate, and platform revealed that American ginseng significantly
hypoxanthine significant differences between groups (Enea modulated serum metabolism, significantly decreasing serum
et al., 2010). creatine kinase and blood urea nitrogen levels (Yan et al.,
Not only is there a difference in metabolism between trained and 2018). Cronin et al. (2018) explored the effects of physical
untrained individuals, but also the same athletes and different levels activity and protein intake on gut microbial composition and
of exercise affect metabolism. Schader et al. (2020) found that slower function, and genomics and metabolomics evaluations revealed
marathon runners with lower levels of aerobic metabolism capacity significant changes in gut microbial composition and function
had drastically altered levels of metabolites, with significant changes with increased physical activity, with the gut virome significantly
in phospholipids and amino acids (Schader et al., 2020). In contrast, changing with increased physical activity in participants who
the metabolomic alterations in good athletes were characterized by received daily supplementation with whey protein (Cronin et al.,
higher levels of phosphatidylcholine after the race (Høeg et al., 2018). Among participants receiving daily whey protein
2020). San-Millan et al. (2020) found increased levels of circulating supplementation, the diversity of the gut virome changed
metabolites in TCA and elevated amplitude of lactate accumulation significantly, suggesting that exercise and nutrition can
in good cyclists (San-Millán et al., 2020). In addition, Prado et al. significantly influence the composition and function of the gut
collected urine samples from football players and analyzed their microbiota. Therefore, metabolomics serves as an assessment
metabolic changes during competition based on an LC-MS tool to facilitate the design of personalized and fine-tuned
platform, identifying 1,091 metabolites, of which 526 metabolites exercise training and nutritional guidance programs for
showed significant changes, including significant increases in the athletes, which can help to maximize athletic performance. In
levels of glucose, uric acid urea, fatty acyls, carboxylic acids, steroids addition, Zhang et al. (2020) explored the effects of a 6-month
and steroid derivatives, and significant decreases in the levels of exercise and dietary intervention on serum metabolites in men
potassium (Khoramipour et al., 2022). Hudson et al. (2021) based on with insomnia symptoms, collecting blood samples from subjects
an NMR platform analyzed the metabolite changes in blood, urine, for metabolite analysis based on a GC-MS platform, and found
and saliva samples of outstanding rugby players, and found that the that the effects of exercise on sleep were mainly related to amino
energy metabolism pathways of rugby, as a sport with high exercise acid, carbohydrate and lipid metabolism, whereas the effects of
intensity, mainly include glycolysis, TCA cycle, and gluconeogenesis diet on sleep were related to carbohydrate, lipid and organic acid
(Hudson et al., 2021). Moreira et al. (2018) analyzed the urinary metabolism (Zhang et al., 2020). Thus, metabolomics provides
metabolites of outstanding swimmers and found that creatine, new insights into the effects of physical activity and diet on
ketone bodies, phosphate, and nitrogen-containing compounds sleep quality.
can be used as urinary metabolites to assess the outstanding
swimmers’ exercise performance, which can be accurately
assessed. Athletes’ performance, which can accurately assess their Exercise metabolomics in chronic disease
physiological status and provide a scientific basis for the prevention and treatment research
development of athletes’ training load programs (Moreira
et al., 2018). Contrepois et al. (2020) analyzed more than 600 metabolite
changes in blood samples collected based on an LC-MS platform
using a variety of histological approaches (targeted and untargeted
The effect of sports nutrition on the metabolomics, lipidomics, proteomics, and transcriptomics), and
body’s metabolism showed that exercise has a significant effect on energy metabolism,
oxidative stress, inflammation, tissue repair and its regulatory
Kirwan et al. (2009) found that post-exercise intake of sugars pathways in diabetic patients (Contrepois et al., 2020). Shi et al.
and caffeine and analysis of metabolite changes in blood samples (2019) found that Exercise can alter myocardial and skeletal muscle
based on an NMR platform revealed a significant decrease in metabolism in heart failure model rats, and the metabolic pathways
blood glucose levels, a significant increase in ketone body levels, of taurine and hypotaurine metabolism and carnitine synthesis have
and a significant increase in plasma levels of lactic acid and a certain regulatory effect on alleviating heart failure, thus providing
alanine (required for gluconeogenesis), which is the first study of an effective target for the treatment of patients with heart failure (Shi
sports nutrition metabolomics (Kirwan et al., 2009). Kozlowska et al., 2019). Siopi et al. (2019) studied the effect of exercise training
et al. (2020) explored the effects of beetroot juice with different intensities on male patients with metabolic syndrome
supplementation on the metabolism of fencing, and urine and collected blood samples to analyze the changes of metabolites
samples were collected to identify changes in metabolites based on the LC-MS platform (Siopi et al., 2019). They found that
based on an LC-MS platform, and significant changes in the resistance training induced the strongest metabolic changes, and the
metabolism of tyrosine, tryptophan, epinephrine, and metabolites of branched-chain amino acids, alanine, carnitine,
norepinephrine were detected, which can help provide a choline, and betaine had larger changes, indicating that exercise
scientific basis for the development of training load programs has beneficial effects on important serum biomarkers in patients
for athlete (Kozlowska et al., 2020). Yan et al. (2018) investigated with metabolic syndrome, which can help optimize the exercise

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guidelines for the people with risk of metabolic syndrome and by increased fuel substrate utilisation, fatty acid β-oxidation,
improve the exercise prescription (Siopi et al., 2019). Palmnas oxidative stress, steroid biosynthesis and protein anabolic
et al. (2018) analyzed the blood samples of obese people based pathways (Cai et al., 2022).
on the NMR platform and found that the obese people had the best Physical activity has many benefits for both physical and
metabolite changes. Blood samples and found that serine and glycine mental health, as studied through metabolomic analysis of
concentrations were lower in the obese population, which can help metabolites released from tissues such as skeletal muscle, bone
to find molecular targets for the treatment of chronic metabolic and liver. These metabolites can influence the body’s metabolic
diseases in obese populations (Palmnäs et al., 2018). Liu et al. (2021) adaptations and improve cardiovascular health, reduce
collected blood samples from children with metabolic syndrome and inflammation and increase muscle mass. Aerobic training
analyzed the changes in metabolites based on the LC-MS platform, increases mitochondrial content and oxidative enzymes, while
and found that exercise combined with dietary interventions resistance training increases muscle fibres and glycolytic
induced 59 metabolites (glycine, serine, and threonine enzymes. Acute exercise leads to changes in amino acid
metabolisms, nitrogen metabolism, TCA cycling, and metabolism, lipid metabolism and cellular energy metabolism
phenylalanine, tyrosine, and tryptophan biosynthesis, etc.) to as well as cofactor metabolism and vitamin metabolism. Chronic
changes, thus providing early diagnostic biomarkers for the exercise leads to changes in amino acid metabolism, lipid
treatment of metabolic diseases such as obesity (Liu et al., 2021). metabolism and nucleotide metabolism and improves lipid
metabolism, thereby improving cardiovascular risk factors and
skeletal muscle adaptations. The study of exercise-induced
Analysis of metabolic pathways by exercise metabolites is a growing field with the potential to reveal
more metabolic mechanisms and tailor exercise programs for
Exercise training induces changes in the body’s metabolic optimal health and exercise performance.
pathways such as lipid metabolism, TCA cycle, glycolysis, amino
acid metabolism, carnitine metabolism, and purine metabolism
(Kelly et al., 2020). Positive effects on cardiovascular health and Potential limitations of exercise
mitochondrial biogenesis exist in populations that engage in chronic metabolomics
low-intensity aerobic training, where energy is produced through
oxidative phosphorylation (Rivera-Brown and Frontera, 2012). Many early exercise metabolomics studies lacked statistical
Therefore, the activation of aerobic metabolic pathways and the rigor, e.g., extensive use of multivariate statistics, small sample
increase in the TCA cycle, fatty acid β-oxidation metabolism and sizes, and a single platform for metabolic analyses (Khoramipour
amino acid metabolism pathways, which allows for the presence of et al., 2022). Furthermore, there were deficiencies in the
lower levels of fatty acids, triglycerides, and cholesterol in the sensitivity and specificity of the biomarkers used in most
organism, can accelerate the utilisation of energy substances and exercise metabolomics studies (Schranner et al., 2021). With
reduce the accumulation of fat, which is conducive to the the continuous advancement of histological technologies,
maintenance of a healthy body weight as well as reducing the metabolomics data alone may not be sufficient to fully
risk of chronic diseases, in addition to increasing the variety of characterize complex physiological changes. There is still
energy substances burned during exercise (Pellegrino et al., 2022). potential for further improvements in the study design of
Chronic metabolic adaptations in prolonged exercise populations many exercise metabolomics studies. In particular, exercise-
typically affect metabolic pathways such as glycolysis, protein related parameters or measurements, such as exercise intensity
synthesis, amino acid consumption, and nucleotides. and exercise duration, have a strong influence on metabolic
In addition to improving muscle strength and metabolic health changes after exercise training. Researchers should incorporate
with short bursts of high-intensity resistance training, it also induces and quantify these parameters more consistently in study
muscle hypertrophy. Resistance training is associated with metabolic designs, which would facilitate comparisons between studies.
changes that contribute to improved anaerobic capacity, muscle Another important goal of exercise metabolomics research is
health, and glycolytic metabolism (Krzysztofik et al., 2019). to routinely use and integrate more histological (proteomics,
Resistance training is mainly dominated by anaerobic metabolic genomics, transcriptomics) techniques in study design.
pathways, with an increase in glycolytic and purine metabolic Metabolomics should not be an “island,” and the integration
pathways. One of the most significant metabolic adaptations of multi-omics data will help researchers to further understand
induced by resistance training is the increase in protein synthesis the interactions between genes, proteins, metabolites, and the
and depletion of amino acids, which are necessary to increase muscle environment, and to gain a deeper understanding of the effects of
mass (Shen et al., 2021; Gehlert et al., 2022). In addition, the exercise on the organism.
pathways involved in nucleotide synthesis—the production of
RNA, DNA and phospholipids required for cellular
membranes—are activated (Pellegrino et al., 2022). There is an Summary and outlook
increase in the rate of ATP hydrolysis and the rate of nucleotide
turnover, an increase in the accumulation of lactic acid in Exercise metabolomics provides researchers in the field of
metabolites following acute resistance training and an increase in exercise science with an effective research tool to search for
the ability to promote glycolytic metabolic adaptations (Gehlert potential biomarkers and therapeutic targets by detecting
et al., 2022). Metabolic adaptations in elite athletes are characterised metabolite changes in a variety of biological fluids and tissues

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after exercise in athletes and patients with chronic diseases, thus Author contributions
helping to improve the practical ability and depth of theoretical
understanding of exercise performance and exercise prevention and SQ: Writing–original draft. XL: Writing–review and editing. JY:
treatment of chronic diseases. Writing–review and editing. LY: Writing–review and editing.
With the continuous maturation of the technology and the
deepening of the research, future exercise metabolomics research
will further evaluate the exercise performance of outstanding Funding
athletes, so that their physiological conditions can be accurately
assessed, which will provide a scientific basis for the development The author(s) declare that financial support was received for the
of precise training load programs for athletes and help coaches to research, authorship, and/or publication of this article. This work
cultivate outstanding athletes in a more effective way. In was supported by a grant from the key program of Shandong
addition, mass spectrometry-based metabolomics testing is Institute of Physical Education Research Start-up Funds
important for the treatment of metabolic disorders and (No. 2390015).
provides clinicians with effective targets for the treatment of
metabolic disorders, which is helpful for the treatment of chronic
metabolic disorders. Meanwhile, mass spectrometry-based Conflict of interest
metabolomics studies will cover more subjects and will
identify more metabolites. It is expected that more points of The authors declare that the research was conducted in the
interest will emerge in the field of exercise metabolism and sports absence of any commercial or financial relationships that could be
nutrition, focusing on the use of metabolomics findings to further construed as a potential conflict of interest.
design personalized and precise nutritional regimens to
maximize the health benefits of physical performance and
exercise. Finally, from the category of research groups, Publisher’s note
exercise metabolomics should focus more on human studies
and more on practical orientated, reality-based experimental All claims expressed in this article are solely those of the authors
designs, collecting non-invasive sample collection methods and do not necessarily represent those of their affiliated
based on urine and saliva. Such a trend will make exercise organizations, or those of the publisher, the editors and the
metabolomics research more informative and popular with reviewers. Any product that may be evaluated in this article, or
participants, and lead to better and more accessible research claim that may be made by its manufacturer, is not guaranteed or
tools for researchers, athletes, and coaches. endorsed by the publisher.

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