European Review for Medical and Pharmacological Sciences 2019; 23: 11011-11019

Sportomics: metabolomics applied to sports.

The new revolution?

T. BONGIOVANNI1, R. PINTUS2, A. DESSÌ2, A. NOTO2, S. SARDO3, G. FINCO3,

G. CORSELLO4, V. FANOS2
1
Nutrition, Hydration & Body Composition Department, Parma Calcio 1913, Parma, Italy
2
Neonatal Intensive Care Unit, Neonatal Pathology and Neonatal Section, University of Cagliari,
Policlinico Universitario, Cagliari, Italy
3
Department of Medical Sciences and Public Health, University of Cagliari, Policlinico Universitario,
Cagliari, Italy
4
Operative Unit of Pediatrics and Neonatal Intensive Therapy, Mother and Child Department,
University of Palermo, Palermo, Italy

Tindaro Bongiovanni and Roberta Pintus contributed equally to this review

Abstract. – Sportomics is the application of this biological matrix, which unlike studies inves-
metabolomics in sports to investigate the met- tigating the effects of fasting, have been shown to
abolic effects of physical exercise on individu- exhibit large inter-subject variability1.
als, whether they are professional athletes or
not. Metabolomics is one of the “omics” scienc-
Physical stress response during or after a train-
es that provide a picture of the metabolic state ing session or a sport challenge alters the equi-
of a person in physiological or pathological con- librium of the biochemical internal environment,
ditions. This is achieved through the analysis of which means that it affects the rate of production
metabolites present in a biological fluid, such as or synthesis and the kinetics of the metabolites
saliva, blood, feces, and urine. The authors re- that are related to exercise intensity and/or muscle
vised the recent literature concerning this topic damage2.
and discussed the useful information that spor-
tomics can provide and the limits of the current Nowadays, the number of metabolomics stud-
experimental settings. Furthermore, in the fu- ies in sport is limited, but they show that resis-
ture, sportomics analyses could be used to pre- tance exercise indicates that continue and intense
vent and manage injuries as it would be known in training lead to modifications in hundreds of me-
advance if an athlete is more prone to experience tabolites in biological fluids, in particular, those
muscular damage or fatigue. Following more tri- associated with extensive lipid mobilization and
als, it would also be possible to set the best di-
et and training programs to get the best perfor-
oxidation. Metabolomics is an all-encompassing
mances out of the athletes. Moreover, based on approach even in this type of investigation and
their metabolic profiles, both adults and chil- could provide new insights and novel biomarkers
dren could choose tailored physical training in with applications to the individual athlete level.
order to preserve and improve their health. Furthermore, the effects on the athletes’ metabo-
lism during or after a particular nutritional regi-
Key Words: men or a given training session can be extensively
Sportomics, Metabolomics, Exercise physiology. studied with this technique3.
For instance, intense training leads to in-
creased levels of metabolites associated with car-
Introduction nitine metabolism and long chain, dicarboxylate,
and essential fatty acid metabolism4, while short-
It is well known that participation in sports and term extensive exercise causes shifts of metabo-
exercise determines modifications in the human lites related to muscle energy consumption and
physiological state. production5.
Exercise, as an external challenge to the human Metabolomics is a holistic, hypothesis-free ap-
metabolome, creates an immediate response (the proach to the investigation of metabolome modi-
turn-over rate being only some seconds) across fication in different pathophysiological situations

Corresponding Author: Roberta Pintus, MSc; e-mail: gomberta@icloud.com 11011

 T. Bongiovanni, R. Pintus, A. Dessì, A. Noto, S. Sardo, G. Finco, G. Corsello, V. Fanos

through powerful data acquisition and advanced The first GC-MS based metabolomics studies
data processing techniques that detect a large were performed in the 1970s, but in 2010 it was
number of metabolites at the same time. In this still considered an emerging field. When some of
context, it can give further insights concerning the earliest exercised-based metabolomics studies
biochemical modifications during physical exer- with human athletes were published, sportomics
cise6. was born3.
Through the analysis of biomolecules present
in tissue samples, cellular extract and biological Sportomics: a Sneak Peek on Physical
fluids, such as saliva, urine, blood, and sweat, Exercise
several hypotheses can be made concerning the Sportomics is the use of “-omics” sciences in
effects of physical exercise or nutrition on the sports and can be combined with clinical labora-
metabolic pathways7. tory analyses. In general, a sportomics approach
The analytical methodologies used in metab- mimics the real challenges and conditions faced
olomics studies are: liquid chromatography cou- during sports training and competition. This ho-
pled with mass spectrometry (LC-MS) and gas listic approach (ex post facto design) is a non-tar-
chromatography coupled with mass spectrom- get analysis using a top-down study model that
etry (GC-MS and nuclear magnetic resonance requires the analysis of large datasets.
(1H-NMR). An important issue in sportomics is statistics:
There can be two types of metabolomics in- useful and fundamental statistical option is to
vestigations: targeted and untargeted. Targeted use non-target analysis (NTA), principal com-
analyses are used to detect metabolites related to ponent analysis (PCA), and probabilistic latent
specific biological processes/pathways that affect semantic analysis (PLSA); these techniques can
a biological function of interest. These methodol- be combined to facilitate a better understanding
ogies have been developed for the identification of metabolites and biomarkers during sportomics
and quantification of amino acids, glycerophos- research9.
pholipids, and acylcarnitines, that are related to In 2011, Resende et al10 proposed the concept
cell energy metabolism. While, non-targeted of sportomics for the first time in a publication,
metabolomics (also known as unbiased, glob- which examined metabolism and cellular re-
al, or discovery metabolomics) employs a wide sponses to different interventions in a windsurfer.
analytical collection and measurement tech- The study showed that the branched chain ami-
niques whereby all detectable metabolites are no acids (BCAA) isoleucine, leucine, and valine
semi-quantified, collected, and prospected for were consumed, and the concentration of these
biomarkers that are indicative of predefined con- BCAAs in the blood decreased by 50% compared
ditions (for instance, metabolites that discrimi- to the resting level during the first round of wind-
nate between diagnosis of diseased and healthy surfing. Even after rest, these concentrations did
individuals). These detected biomarkers could not increase, reaching approximately 30% of their
indicate causative and/or associative relationships resting concentration after the second round of
with a physiological state of interest, allowing the exercise. Aromatic amino acids were consumed
investigation of the effects on the metabolism of at lower levels and decreased less than BCAAs.
a given stimulus, providing an early diagnosis A brief summary of the most important studies
or prognosis and even to detect the efficacy of a concerning sportomics with the main results are
specific therapeutic treatment. One of the biggest listed in Table I.
challenges of non-targeted metabolomics is the Since untargeted sportomics is non-hypoth-
precise detection, identification, and quantifica- esis-driven research on an individual’s metabo-
tion of a metabolite of interest. The application lite changes during sports and exercise, can aid
of modern high-resolution mass analyzers, such athletes, coaches, technical, and medical staff 9.
as time-of-flight and the Orbitrap, has improved For example, de Almeida et al26 and Prado et al27
analyte identification with the ability to measure proposed that acute use of KAAA (ketoanalogues
mass-to-charge ratios (m/z) with an error of fewer associated with amino acids) can lower the am-
than 10 parts per million (<0.001%). Highly ac- monemia increase caused by endurance exercise
curate measured masses can then be compared to in humans and 28. Gonçalves et al28 showed that
open-source databases and consequently be given an increase in ammonemia and a corresponding
a tentative identification for a molecule’s name/ rise in lymphocytes are both decreased through
structure8. arginine supplementation.

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 Sportomics: metabolomics applied to sports. The new revolution?

Table I. Most important sportomics studies with main findings.

Authors Athletes Samples Methods Metabolites results

Yan 16 male professional Serum GC/TOF-MS Metabolites responsible for classification based on age and
(2009)11 rowers of different training level: alanine, lactate, beta-dimethyl glucopyranoside,
ages, 12 controls pyroglutamic acid, cysteine, glutamic acid, citric acid, free fatty
acids, valine, glutamine

Pechilvanis 12 men, short run Urine 1

H-NMR Modification in lactate, pyruvate, alanine, and BCAA
(2010)6
Lehmann 29 healthy non-profes- Plasma LC-MS Octanoyl-, decanoyl-, and dodecanoyl-carnitine
(2010)12 sional runners

Lewis 25 Boston marathon Plasma LC-MS Glycerol, niacinamide, glucose-6-phosphate, pantothenate,

(2010)13 runners vs. 302 succinate
longitudinal cohort
study subjects

Enea 22 women Urine 1

H-NMR Acetate in trained athletes
(2010)5 10 untrained
12 trained short term
intense physical
exercise

Ciborowski 20 divers Plasma LC-MS Lysophosphatidylcholines, lysophosphatydiletanholamine,

(2010)14 lysoplasmalogens, and hemolysis related compounds

Zauber 1060 km no stop Saliva LC-MS Creatinine, glucose and antioxidative mechanisms related me-
(2012)15 cycling events tabolites

Yde 12 milk protein vs. 8 Plasma 1

H-NMR No difference
(2013)16 control in high
resistance exercise

Morris 214 healthy adults Urine 1

H-NMR Amino acids in the low fitness group
(2013)17 divided according to
their fitness levels

Mukherjee 9 competitive cyclists Urine 1

H-NMR Different concentration of: 2-hydroxyisovalerate, acetate,
(2014)18 vs. 8 minimally active malonate, hypoxanthine, formate, glycine, fumarate, tryptophan
males 50-60 years old

Nieman 19 trained male Plasma GC-MS 13- and 9-hydroxyoctadecanoic acid

(2014)19 cyclists LC-MS
Peake 20 cyclist and triath- Plasma GC-MS  TCA intermediates, monounsaturated fatty acids
(2014)20 letes, different training after high-intensity training
protocols
Amino acids in both moderate and high-intensity training

Lou 6 healthy sedentary Urine LC-TOF/MS 1-methyladenosine, 5-methylthoiadenosine

(2014)21 man from 0 to 3000 m 3-indoleacetic and L-glutamic acid
altitude
Wang 12 professional half Serum GC/ TOF- TMAO, phenylalanine lactate, alanine, trimethylamine,
(2015)22 pipe snowboarders MS malonate, taurine, glycine
Daskalaki 3 physically active Urine LC-MS Modification in purine, tryptophan, carnitine, cortisol and andro-
(2015)1 males gen pathways, amino acid oxidation and gut microbiota related
metabolites
Karl 25 male soldiers, 4 Plasma UPLC-MS Free fatty acids, TCA metabolites and BCAA
(2017)23 days ski-march Monoacylglycerols, lipid metabolism

Table continued

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 T. Bongiovanni, R. Pintus, A. Dessì, A. Noto, S. Sardo, G. Finco, G. Corsello, V. Fanos

Table I. Continued. Most important sportomics studies with main findings.

Authors Athletes Samples Methods Metabolites results

Messier 20 endurance exercise Plasma 1

H-NMR Glucose, glutamine, alanine, and BCAA at 2150 m
(2017)24 at sea level and
2150 m above
Berton 10 young male Serum 1
H-NMR  2-hydroxybutyrate, 2-oxoisocaproate,
(2017)25 athletes, resistance 3-hydroxyisobutirate,
exercise alanine, hypoxanthine, pyruvate, succinate

Isoleucine, leucine, lysine, ornithine, valine

Nieman 24 male runners to Plasma UHPLC-MS/ Carnitine, 13 methylmuristic acid, sebacate
(2017)3 exhaustion MS

Camerino et al29 suggested that KAAA sup- meaningful metabolite variations, authors iden-
plementation decreases ammonia concentration tified glucose, citrate, acetate, leucine, ornithine,
during high-intensity exercise but does not affect myo-inositol, lactate, and glutamate.
physical or cognitive-motor performances under a Enea et al5 explored the profile of metabolite
low heat stress environment. changes due to acute physical exercise5. They de-
Smith and Hill30, observed changes for com- scribed a global picture of the effects of two types
pounds related to ATP-PCr and glycolytic sys- of exhaustive exercise (short term and prolonged)
tems and recently Dudzinska et al31 showed that on the metabolic urinary profile of untrained (ten
a standardized physical exercise with increasing recreational women) and (12 elite athletes) trained
intensity leads to an increase in IMP (inosine women. They found that creatinine excretion is
nucleotides) concentration in red blood cells im- not affected by physical exercise in the urine. Cre-
mediately after exercise which, with a significant atinine concentration is associated with diet and
increase in the ATP/ADP and ADP/AMP ratios, muscle mass, but they observed the difference in
indicates an increase in the phosphorylation of creatinine excretion between trained and untrained
AMP and ADP to ATP. women. TMAO (trimethylamine-N-oxide, a bio-
Yan et al11 demonstrated that long-term endur- marker of ischemic medullar renal injury) was at
ance and strength training exert different effects a very low level both at rest and after exercise.
on the metabolism of athletes of different exercise They observed an increase in urine excretion of al-
seniority, and training stage-related trajectory of anine, hypoxanthine, lactate, acetate, and lactate/
the two groups of athletes was clearly shown along pyruvate ratio (suggesting tissue hypoxia) after the
with training time. However, most of these varia- short-term intensive exercise test. Prolonged exer-
tions were not observed by common biochemical cise does not change urinary metabolic profiles.
parameters. The identified metabolites contribut- A pilot study was conducted on three physi-
ing to the classification included alanine, lactate, cally active, non-smoking males, engaged in a
beta-d-methylglucopyranoside, pyroglutamic acid, two-day (37 h) well-designed trial, where aerobic
cysteine, glutamic acid, citric acid, free fatty acids, exercise was performed on the first day and ath-
valine, glutamine, phenylalanine, tyrosine, and so letes rested on the second day1. The urine sam-
on, which were involved in glucose metabolism, ples were collected at regular intervals across five
oxidative stress, energy metabolism, lipid metab- time points every day and showed that significant
olism, and amino acid metabolism. metabolites involved in different pathways were
Santone et al32 investigated the variation in affected by exercise: purine pathway, tryptophan
metabolic content of saliva in the presence of a metabolism, carnitine (increase of fatty acid car-
physical stress (the Yo-Yo IR test) in fourteen pro- nitine conjugates), glucose metabolism with an
fessional soccer players from the Italian Lega Pro increase of pyruvate after exercise, increase of
team (C1). For every athlete two samples of sali- some microflora’s synthesis metabolites, as well
va were collected: one before and one after the as an increase of keto acids. The final major group
test. The NMR spectra of saliva offer a metab- varying between first pre-exercise and post was a
olites profiling which was analyzed by Principal series of urinary steroid metabolites as urocorti-
Component Analysis as a blind test. Among the sol glucuronide1.

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 Sportomics: metabolomics applied to sports. The new revolution?

A non-targeted, 1H NMR-based metabonomic tigations12,13,16,25,33 have focused on the metabolic

analysis of urine samples obtained from twelve changes inducted from endurance exercises and
young, moderately trained, healthy males before resistance exercises. Metabolomics approach was
and after two exercise sessions (repeated sprints), also used for supporting medicinal value26. Me-
differing in the duration of the rest interval (10 tabolomics approach, using gas chromatography
seconds or 1 minute) between repeated efforts, mass spectrometry (GC-MS) and orthogonal par-
showed6 that physical exercise caused dramat- tial least square discriminant analysis (OPLS-DA)
ic changes in the urine metabolome; hence, post was used to discriminate between chronic local-
exercise urine provided very different profiles ized pain and chronic widespread pain34.
compared to pre-exercise urine. Even after the NMR-based metabolomics investigations were
exclusion of the lactate signal, PCA alone could applied to depict the metabolic profiles of urine
differentiate from pre-exercise to post-exercise samples, which were collected from young ath-
urine. Separation of the 10 seconds from the letes at three-time points including the time be-
1-minute rest interval was mainly due to lactate, fore exercises, the time before a series of exhaus-
pyruvate, alanine, compounds of the Krebs cycle, tive physical exercises followed by short-term
2-oxoacids of BCAA, and 2-hydroxybutyrate. All rest, and after the treatment of acupuncture, or
of these metabolites increased more with the short taking an extended rest35.
compared to the long interval, thus supporting the Nieman et al19 used a metabolomics approach
hypothesis that the former elicited greater meta- to study the changes in plasma of two bioac-
bolic disturbances than the latter as a result of the tive oxidized linoleic acid metabolites: 13-hy-
very limited time available for recovery6. droxy-octadecadienoic acid and 9-hydroxy-octa-
Coelho et al2 used the sportomics approach to decadienoic acid following a 75-km cycling bout
evaluate biochemical and hematological changes in 19 male cyclists. In the same year, Mukherjee
in response to a combined training session in four et al18 used an NMR spectroscopy-based metab-
male world-class rowers. olomics to characterize the metabolic adaptive
More recently, a metabolomic study by Messi- pathways altered by exercise in veteran athletes,
er et al24 found that, at similar exercise intensity, 50-60-year-old males, and age-matched untrained
substrate use during endurance exercise differed individuals.
between SL (sea level) and moderate altitude of An untargeted metabolomics approach was
2150 meters. It appears that BCAAs were used to used to develop a compliance measure in urine to
maintain glycaemia during endurance exercise at distinguish between two dietary patterns36.
moderate altitude. To gain insights into adaptive physiological
Recent research has generated fascinating me- processes and to study the variations in metabo-
tabolomic data; Lou et al21 found changes in ener- lites of energy mobilization, Zauber et al15 report
gy pathways (lipid metabolism), and an increase the adaptive processes through the collection of
in purine metabolic products at altitudes of 3,000- saliva, from male and female athletes, at four
4,000 meters in six healthy, sedentary men, when time points in the daytime, throughout a 1060 km
compared with a condition of normoxia. nonstop cycling event and taking the saliva over 3
In 2017, Berton et al25 postulated that, to im- days before the event and throughout the follow-
prove the understanding of the metabolic re- ing two days. Using a mass spectrometry-based
sponse after resistance exercise, the employment approach, they found that during the workout
of metabolomics can be essential, allowing for a there was an increase of proteins with redox-reg-
broader and better understanding of the metabolic ulatory function and of lysozyme and amylase;
response in a biological system. In addition, also while during the recovery phase, there was an in-
due to their untargeted approach, metabolomics crease of immunoglobulins.
may allow for the identification of changes in con- The metabolomic approach was previously
centrations of metabolites that have not yet been used14 to evaluate the effect of increased pressure
described, as well as generating new hypotheses equivalent to diving at 30 and 60 meters for 30
(e.g., mechanism of muscle hypertrophy and ener- minutes in two groups of divers using an untar-
gy supply) and the discovery of novel biomarkers. geted approach with LC-MS fingerprinting of
Several researches used a metabolomic ap- plasma.
proach to gain a comprehensive view of the me- As reported in a recent review, the metabolom-
tabolome and its modulation by different types, ics analysis revealed exercise-induced changes in
intensity, duration of exercise. Published inves- 209 metabolites, with a predominance of post-ex-

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 T. Bongiovanni, R. Pintus, A. Dessì, A. Noto, S. Sardo, G. Finco, G. Corsello, V. Fanos

ercise increase in plasma long-and medium-chain levels of succinate were observed, as well as an in-
fatty acids, fatty acid oxidation products (dicar- creased TMAO, that may be due to increased food
boxylate and monohydroxy fatty acids, acylcarni- intake in daily diet. Moreover, heightened levels of
tines), and ketone bodies. Perturbations in many hippurate and phenylalanine indicate a metabolic
of these metabolites were still apparent in endur- adaption in the athlete as a response to the elevat-
ance athletes after 14 h of recovery. The relation- ed training load. Interesting, the PCA score plot
ship between increases in plasma IL-6 and these showed the tendency to separate athletes with dif-
lipid metabolites were also tested, but no viable ferent training amounts and intensities.
statistical model could be established3. Peake et al20 compared the metabolic responses
In a recent study, Nieman et al4 use metabo- after high-intensity interval and continuous, mod-
lomics profiling and bioinformatics technologies erately intense cycling matched for total workload.
to evaluate the relationship of exercise-induced Targeted gas chromatography-mass spectrometry
increases in plasma IL-6 and lipid-related metab- (GS-MS)-based metabolomic analysis was used
olites in 24 athletes who ran on treadmills to ex- to assess changes, in blood samples, in tricarbox-
haustion at high intensity. ylic acid (TCA) intermediates, fatty acids, ami-
Global measurement of metabolites could be no acids, ACTH, cortisol, catecholamine, growth
applied to help understand the athlete’s current hormone, glucagon, IL-6, and insulin in ten well-
state, such as fatigue, physical capacity, etc., or for trained male cyclists and triathletes. The results
use in aiding prediction of future events, such as showed that of 49 metabolites identified and
talent identification, onset of illness, susceptibil- quantified in plasma, 11 changed after both two
ity to injury or impaired physical performance8. types of exercise: high-intensity interval training
Karl et al23 showed that high physical activi- (HIIT) and continuous, moderate-intensity cy-
ty and a short-term but severe energy deficit, in cling training, 13 changed only after HIIT, and
25 male soldiers, elicited pronounced changes in 5 changed only after moderate-intensity cycling
plasma metabolite profiles that were consistent exercises. Notable changes included substan-
with an increase in energy metabolism, lipolysis, tial increases in tricarboxylic acid intermediates
fatty acid oxidation, and ketogenesis. Of 737 iden- and monounsaturated fatty acids after HIIT and
tified metabolites (performing nontargeted glob- marked decreases in amino acids during recovery
al metabolite profiling in plasma), 478 changed from both trials. Plasma ACTH, cortisol, and GH
during the training (13 km/day for 4 days, were all higher immediately after HIIT. Morris
cross-country ski march carrying a backpack that et al17 examined the relationship between fitness
weighted around 45 kg). Increases in 88% of the level, substrate oxidation rates, and the metabol-
free fatty acids and 91% of the acylcarnitines and ic profile in 214 healthy adults. The metabolomic
decrease in 88% of the mono-and diacylglycerols analysis showed that adults with increased fitness
detected within lipid metabolism pathways were levels and raised fat oxidation rate during exercise
observed. Smaller increases in 75% of the tricar- excreted less amino acids than adults with lower
boxylic acid cycle intermediates, and 50% of the fitness levels and higher insulin resistance.
branched amino acid metabolites detected were
also observed23.
Furthermore, Andersson Hall et al37 used plas- Conclusions and
ma NMR-metabolomics to investigate fat oxida- Future Perspectives
tion in different conditions (fasting, control and
after an exercise and 2 h of fasting recovery). Au- Over the past 7 years sportomics was used to
thors showed for the first time that training after investigate a wide range of sports and physical
2 hours of fasting recovery from a previous bout exercise, highlighting the metabolic shifts in ath-
will increase fat oxidation showing that prior ex- letes of all ages and with different level of fitness.
ercise is a potent stimulator of fat oxidation in a Several biomarkers of oxidative stress, muscular
following training session. damage, and energy deficit could be proposed in
Wang et al22 explored how physical exercise the future in order to prevent injuries and fatigue
(1-week of adaptative training followed by three syndrome.
weeks of training) impacts and changes metabo- In addition, recent advantages in metabolomics
lite profiles in twelve professional half-pipe snow- will add metabolites with autocrine, paracrine or
boarders, using nontargeted 1H NMR-based me- endocrine function to the contraction-induced se-
tabolomics analyses of urine samples. Decreased cretome of the skeletal muscle. The identification

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 Sportomics: metabolomics applied to sports. The new revolution?

of these metabolites will lead to a more compre- the cellular and metabolic responses of world-
hensive view described by a new myo(metabo) class canoeists training: a sportomics approach.
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concept in metabolic studies and exercise sci-
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Conflict of Interests 10) Resende NM, de Megalhães Neto AM, Bachini F, de
The Authors declare that they have no conflict of interests. C astro LE, Bassini A, C ameron LC. Metabolic chang-
es during a field experiment in a world-class wind-
surfing athlete: a trial with multivariate analyses.
Authors’ contributions OMICS 2011; 15: 695-704.
TB reviewed the recent literature. RP analyzed and orga- 11) Yan B, A J, Wang G, Lu H, Huang X, L iu Y, Zha W,
nized data in table. All other authors read and approved the Hao H, Zhang Y, L iu L, Gu S, Huang Q, Zheng Y,
Sun J. Metabolomic investigation into variation of
final manuscript. endogenous metabolites in professional athletes
subject to strength-endurance training. J Appl
Physiol 2009; 106: 531-538.
Funding
12) L ehmann R, Zhao X, Weigert C, Simon P, Fehrenbach
This research received no external funding.
E, Fritsche J, M achann J, Schick F, Wang J, Hoene M,
Schleicher ED, Häring HU, Xu G, Niess AM. Medium
chain acylcarnitines dominate the metabolite pat-
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