BACKGROUND: Physical activity (PA) provides health benefits across the lifespan and improves many established cardiovascular risk factors that have a significant impact on overall mortality. However, discrepancies between self-reported and device-based measures of PA make it difficult to obtain consistent results regarding PA and its health effects. Moreover, PA may produce different health effects depending on the type, intensity, duration, and frequency of activities and individual factors such as age, sex, body weight, early life conditions/exposures, etc. Appropriate biomarkers relating the degree of PA level with its effects on health, especially in children and adolescents, are required and missing. The main objective of the INTEGRActiv study is to identify novel useful integrative biomarkers of PA and its effects on the body health in children and adolescents, who represent an important target population to address personalized interventions to improve future metabolic health. METHODS/DESIGN: The study is structured in two phases. First, biomarkers of PA and health will be identified at baseline in a core cohort of 180 volunteers, distributed into two age groups: prepubertal (n = 90), and postpubertal adolescents (n = 90). Each group will include three subgroups (n = 30) with subjects of normal weight, overweight, and obesity, respectively. Identification of new biomarkers will be achieved by combining physical measures (PA and cardiorespiratory and muscular fitness, anthropometry) and molecular measures (cardiovascular risk factors, endocrine markers, cytokines and circulating miRNA in plasma, gene expression profile in blood cells, and metabolomics profiling in plasma). In the second phase, an educational intervention and its follow-up will be carried out in a subgroup of these subjects (60 volunteers), as a first validation step of the identified biomarkers. DISCUSSION: The INTEGRActiv study is expected to provide the definition of PA and health-related biomarkers (PA-health biomarkers) in childhood and adolescence. It will allow us to relate biomarkers to factors such as age, sex, body weight, sleep behavior, dietary factors, and pubertal status and to identify how these factors quantitatively affect the biomarkers' responses. Taken together, the INTEGRActiv study approach is expected to help monitor the efficacy of interventions aimed to improve the quality of life of children/adolescents through physical activity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, Identifier NCT05907785.

C2VN INSERM INRAE Aix Marseille University Marseille France

CIBER de Fisiopatología de la Obesidad y Nutrición Madrid Spain

Department of Pediatrics Fundación de Investigación Consorcio Hospital General University of Valencia Valencia Spain

Health Research Institute of the Balearic Islands Palma Spain

Human and Animal Physiology Wageningen University Wageningen Netherlands

Laboratory of Adipose Tissue Biology Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Molecular Biology Nutrition and Biotechnology Palma Spain

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Fogelholm M. Physical activity, fitness and fatness: relations to mortality, morbidity and disease risk factors. A systematic review. Obes Rev. (2010) 11(3):202–21. 10.1111/j.1467-789X.2009.00653.x PubMed DOI

Reiner M, Niermann C, Jekauc D, Woll A. Long-term health benefits of physical activity–a systematic review of longitudinal studies. BMC Public Health. (2013) 13:813. 10.1186/1471-2458-13-813 PubMed DOI PMC

Daskalopoulou C, Stubbs B, Kralj C, Koukounari A, Prince M, Prina AM. Physical activity and healthy ageing: a systematic review and meta-analysis of longitudinal cohort studies. Ageing Res Rev. (2017) 38:6–17. 10.1016/j.arr.2017.06.003 PubMed DOI

Zakari M, Alsahly M, Koch LG, Britton SL, Katwa LC, Lust RM. Are there limitations to exercise benefits in peripheral arterial disease? Front Cardiovasc Med. (2018) 5:173. 10.3389/fcvm.2018.00173 PubMed DOI PMC

Galmes-Panades AM, Bennasar-Veny M, Oliver P, Garcia-Coll N, Chaplin A, Fresneda S, et al. Efficacy of different modalities and frequencies of physical exercise on glucose control in people with prediabetes (GLYCEX randomised trial). Metabolites. (2022) 12(12):1286. 10.3390/metabo12121286 PubMed DOI PMC

Zieker D, Fehrenbach E, Dietzsch J, Fliegner J, Waidmann M, Nieselt K, et al. cDNA microarray analysis reveals novel candidate genes expressed in human peripheral blood following exhaustive exercise. Physiol Genomics. (2005) 23(3):287–94. 10.1152/physiolgenomics.00096.2005 PubMed DOI

Janssen JJE, Lagerwaard B, Nieuwenhuizen AG, Escote X, Canela N, Del Bas JM, et al. Single and joined behaviour of circulating biomarkers and metabolic parameters in high-fit and low-fit healthy females. Int J Mol Sci. (2023) 24(4):4202. 10.3390/ijms24044202 PubMed DOI PMC

Magnussen CG, Smith KJ, Juonala M. When to prevent cardiovascular disease? As early as possible: lessons from prospective cohorts beginning in childhood. Curr Opin Cardiol. (2013) 28(5):561–8. 10.1097/HCO.0b013e32836428f4 PubMed DOI

WHO Guidelines on physical activity and sedentary behaviour. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO.

Gutin B, Owens S. The influence of physical activity on cardiometabolic biomarkers in youths: a review. Pediatr Exerc Sci. (2011) 23(2):169–85. 10.1123/pes.23.2.169 PubMed DOI

Katzmarzyk PT, Barreira TV, Broyles ST, Champagne CM, Chaput JP, Fogelholm M, et al. Physical activity, sedentary time, and obesity in an international sample of children. Med Sci Sports Exerc. (2015) 47(10):2062–9. 10.1249/MSS.0000000000000649 PubMed DOI

de Mello VD, Kolehmanien M, Schwab U, Pulkkinen L, Uusitupa M. Gene expression of peripheral blood mononuclear cells as a tool in dietary intervention studies: what do we know so far? Mol Nutr Food Res. (2012) 56(7):1160–72. 10.1002/mnfr.201100685 PubMed DOI

Reynes B, Priego T, Cifre M, Oliver P, Palou A. Peripheral blood cells, a transcriptomic tool in nutrigenomic and obesity studies: current state of the art. Compr Rev Food Sci Food Saf. (2018) 17(4):1006–20. 10.1111/1541-4337.12363 PubMed DOI

Caimari A, Oliver P, Rodenburg W, Keijer J, Palou A. Slc27a2 expression in peripheral blood mononuclear cells as a molecular marker for overweight development. Int J Obes (Lond). (2010) 34(5):831–9. 10.1038/ijo.2010.17 PubMed DOI

Oliver P, Reynes B, Caimari A, Palou A. Peripheral blood mononuclear cells: a potential source of homeostatic imbalance markers associated with obesity development. Pflugers Arch. (2013) 465(4):459–68. 10.1007/s00424-013-1246-8 PubMed DOI

Konieczna J, Sanchez J, van Schothorst EM, Torrens JM, Bunschoten A, Palou M, et al. Identification of early transcriptome-based biomarkers related to lipid metabolism in peripheral blood mononuclear cells of rats nutritionally programmed for improved metabolic health. Genes Nutr. (2014) 9(1):366. 10.1007/s12263-013-0366-2 PubMed DOI PMC

Diaz-Rua R, Keijer J, Caimari A, van Schothorst EM, Palou A, Oliver P. Peripheral blood mononuclear cells as a source to detect markers of homeostatic alterations caused by the intake of diets with an unbalanced macronutrient composition. J Nutr Biochem. (2015) 26(4):398–407. 10.1016/j.jnutbio.2014.11.013 PubMed DOI

Sanchez J, Priego T, Pico C, Ahrens W, De Henauw S, Fraterman A, et al. Blood cells as a source of transcriptional biomarkers of childhood obesity and its related metabolic alterations: results of the IDEFICS study. J Clin Endocrinol Metab. (2012) 97(4):E648–52. 10.1210/jc.2011-2209 PubMed DOI

Jang K, Tong T, Lee J, Park T, Lee H. Altered gene expression profiles in peripheral blood mononuclear cells in obese subjects. Obes Facts. (2020) 13(3):375–85. 10.1159/000507817 PubMed DOI PMC

Costa A, Reynes B, Konieczna J, Martin M, Fiol M, Palou A, et al. Use of human PBMC to analyse the impact of obesity on lipid metabolism and metabolic status: a proof-of-concept pilot study. Sci Rep. (2021) 11(1):18329. 10.1038/s41598-021-96981-6 PubMed DOI PMC

Janssen JJE, Lagerwaard B, Porbahaie M, Nieuwenhuizen AG, Savelkoul HFJ, van Neerven RJJ, et al. Extracellular flux analyses reveal differences in mitochondrial PBMC metabolism between high-fit and low-fit females. Am J Physiol Endocrinol Metab. (2022) 322(2):E141–E53. 10.1152/ajpendo.00365.2021 PubMed DOI PMC

Sanchez J, Pico C, Ahrens W, Foraita R, Fraterman A, Moreno LA, et al. Transcriptome analysis in blood cells from children reveals potential early biomarkers of metabolic alterations. Int J Obes (Lond). (2017) 41(10):1481–8. 10.1038/ijo.2017.132 PubMed DOI

Szostaczuk N, van Schothorst EM, Sanchez J, Priego T, Palou M, Bekkenkamp-Grovenstein M, et al. Identification of blood cell transcriptome-based biomarkers in adulthood predictive of increased risk to develop metabolic disorders using early life intervention rat models. FASEB J. (2020) 34(7):9003–17. 10.1096/fj.202000071RR PubMed DOI

Galmes S, Ruperez AI, Sanchez J, Moreno LA, Foraita R, Hebestreit A, et al. KLB and NOX4 expression levels as potential blood-based transcriptional biomarkers of physical activity in children. Sci Rep. (2023) 13(1):5563. 10.1038/s41598-023-31537-4 PubMed DOI PMC

Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem. (2010) 285(23):17442–52. 10.1074/jbc.M110.107821 PubMed DOI PMC

Zhou Q, Shi C, Lv Y, Zhao C, Jiao Z, Wang T. Circulating microRNAs in response to exercise training in healthy adults. Front Genet. (2020) 11:256. 10.3389/fgene.2020.00256 PubMed DOI PMC

Silva GJJ, Bye A, El Azzouzi H, Wisloff U. MicroRNAs as important regulators of exercise adaptation. Prog Cardiovasc Dis. (2017) 60(1):130–51. 10.1016/j.pcad.2017.06.003 PubMed DOI

Wang L, Lv Y, Li G, Xiao J. MicroRNAs in heart and circulation during physical exercise. J Sport Health Sci. (2018) 7(4):433–41. 10.1016/j.jshs.2018.09.008 PubMed DOI PMC

Landrier JF, Derghal A, Mounien L. MicroRNAs in obesity and related metabolic disorders. Cells. (2019) 8(8):859. 10.3390/cells8080859 PubMed DOI PMC

Dimassi S, Karkeni E, Laurant P, Tabka Z, Landrier JF, Riva C. Microparticle miRNAs as biomarkers of vascular function and inflammation response to aerobic exercise in obesity? Obesity (Silver Spring). (2018) 26(10):1584–93. 10.1002/oby.22298 PubMed DOI

Pico C, Serra F, Rodriguez AM, Keijer J, Palou A. Biomarkers of nutrition and health: new tools for new approaches. Nutrients. (2019) 11(5):1092. 10.3390/nu11051092 PubMed DOI PMC

Kelly RS, Kelly MP, Kelly P. Metabolomics, physical activity, exercise and health: a review of the current evidence. Biochim Biophys Acta Mol Basis Dis. (2020) 1866(12):165936. 10.1016/j.bbadis.2020.165936 PubMed DOI PMC

Horakova O, Hansikova J, Bardova K, Gardlo A, Rombaldova M, Kuda O, et al. Plasma acylcarnitines and amino acid levels as an early complex biomarker of propensity to high-fat diet-induced obesity in mice. PLoS One. (2016) 11(5):e0155776. 10.1371/journal.pone.0155776 PubMed DOI PMC

Li VL, He Y, Contrepois K, Liu H, Kim JT, Wiggenhorn AL, et al. An exercise-inducible metabolite that suppresses feeding and obesity. Nature. (2022) 606(7915):785–90. 10.1038/s41586-022-04828-5 PubMed DOI PMC

Karstoft K, Pedersen BK. Skeletal muscle as a gene regulatory endocrine organ. Curr Opin Clin Nutr Metab Care. (2016) 19(4):270–5. 10.1097/MCO.0000000000000283 PubMed DOI

Leal LG, Lopes MA, Batista ML, Jr. Physical exercise-induced myokines and muscle-adipose tissue crosstalk: a review of current knowledge and the implications for health and metabolic diseases. Front Physiol. (2018) 9:1307. 10.3389/fphys.2018.01307 PubMed DOI PMC

Li F, Li Y, Duan Y, Hu CA, Tang Y, Yin Y. Myokines and adipokines: involvement in the crosstalk between skeletal muscle and adipose tissue. Cytokine Growth Factor Rev. (2017) 33:73–82. 10.1016/j.cytogfr.2016.10.003 PubMed DOI

de Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ. (2007) 85(9):660–7. 10.2471/BLT.07.043497 PubMed DOI PMC

Costa A, van der Stelt I, Reynes B, Konieczna J, Fiol M, Keijer J, et al. Whole-genome transcriptomics of PBMC to identify biomarkers of early metabolic risk in apparently healthy people with overweight-obesity and in normal-weight subjects. Mol Nutr Food Res. (2023) 67(4):e2200503. 10.1002/mnfr.202200503 PubMed DOI

Morgan JF, Reid F, Lacey JH. The SCOFF questionnaire: a new screening tool for eating disorders. West J Med. (2000) 172(3):164–5. 10.1136/ewjm.172.3.164 PubMed DOI PMC

Banos RM, Cebolla A, Etchemendy E, Felipe S, Rasal P, Botella C. Validation of the Dutch eating behavior questionnaire for children (DEBQ-C) for use with spanish children. Nutr Hosp. (2011) 26(4):890–8. 10.1590/S0212-16112011000400032 PubMed DOI

Cook S, Auinger P, Huang TT. Growth curves for cardio-metabolic risk factors in children and adolescents. J Pediatr. (2009) 155(3):S6.e15–26. 10.1016/j.jpeds.2009.04.051 PubMed DOI PMC

European Food Safety Authority, 2014. Guidance on the EU menu methodology. EFSA Journal. (2014) 12(12):3944. 80 pp.

Serra-Majem L, Ribas L, Ngo J, Ortega RM, Garcia A, Perez-Rodrigo C, et al. Food, youth and the Mediterranean diet in Spain. Development of KIDMED, Mediterranean diet quality index in children and adolescents. Public Health Nutr. (2004) 7(7):931–5. 10.1079/PHN2004556 PubMed DOI

Altavilla C, Caballero-Perez P. An update of the KIDMED questionnaire, a Mediterranean diet quality Index in children and adolescents. Public Health Nutr. (2019) 22(14):2543–7. 10.1017/S1368980019001058 PubMed DOI PMC

Mackelvie KJ, McKay HA, Khan KM, Crocker PR. A school-based exercise intervention augments bone mineral accrual in early pubertal girls. J Pediatr. (2001) 139(4):501–8. 10.1067/mpd.2001.118190 PubMed DOI

Kowalski CK, Crocker PR, Kowalski NP. Convergent validity of the physical activity questionnaire for adolescents. Pediatr Exerc Sci. (1997) 9:342–52. 10.1123/pes.9.4.342 DOI

Bailey DA, McKay HA, Mirwald RL, Crocker PR, Faulkner RA. A six-year longitudinal study of the relationship of physical activity to bone mineral accrual in growing children: the university of Saskatchewan bone mineral accrual study. J Bone Miner Res. (1999) 14(10):1672–9. 10.1359/jbmr.1999.14.10.1672 PubMed DOI

Rey-Lopez JP, Ruiz JR, Ortega FB, Verloigne M, Vicente-Rodriguez G, Gracia-Marco L, et al. Reliability and validity of a screen time-based sedentary behaviour questionnaire for adolescents: the HELENA study. Eur J Public Health. (2012) 22(3):373–7. 10.1093/eurpub/ckr040 PubMed DOI

Chervin RD, Hedger K, Dillon JE, Pituch KJ. Pediatric sleep questionnaire (PSQ): validity and reliability of scales for sleep-disordered breathing, snoring, sleepiness, and behavioral problems. Sleep Med. (2000) 1(1):21–32. 10.1016/S1389-9457(99)00009-X PubMed DOI

Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescent, National Heart, Lung and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. (2011) 128 (Suppl 5):S213–56. 10.1542/peds.2009-2107C PubMed DOI PMC

Lurbe E, Agabiti-Rosei E, Cruickshank JK, Dominiczak A, Erdine S, Hirth A, et al. 2016 European society of hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens. (2016) 34(10):1887–920. 10.1097/HJH.0000000000001039 PubMed DOI

Ross R, Blair SN, Arena R, Church TS, Despres JP, Franklin BA, et al. Importance of assessing cardiorespiratory fitness in clinical practice: a case for fitness as a clinical vital sign: a scientific statement from the American heart association. Circulation. (2016) 134(24):e653–99. 10.1161/CIR.0000000000000461 PubMed DOI

Lang JJ, Belanger K, Poitras V, Janssen I, Tomkinson GR, Tremblay MS. Systematic review of the relationship between 20 m shuttle run performance and health indicators among children and youth. J Sci Med Sport. (2018) 21(4):383–97. 10.1016/j.jsams.2017.08.002 PubMed DOI

Ortega FB, Ruiz JR, Castillo MJ, Sjostrom M. Physical fitness in childhood and adolescence: a powerful marker of health. Int J Obes (Lond). (2008) 32(1):1–11. 10.1038/sj.ijo.0803774 PubMed DOI

Hogstrom G, Nordstrom A, Nordstrom P. High aerobic fitness in late adolescence is associated with a reduced risk of myocardial infarction later in life: a nationwide cohort study in men. Eur Heart J. (2014) 35(44):3133–40. 10.1093/eurheartj/eht527 PubMed DOI

Santana CCA, Azevedo LB, Cattuzzo MT, Hill JO, Andrade LP, Prado WL. Physical fitness and academic performance in youth: a systematic review. Scand J Med Sci Sports. (2017) 27(6):579–603. 10.1111/sms.12773 PubMed DOI

Lubans D, Richards J, Hillman C, Faulkner G, Beauchamp M, Nilsson M, et al. Physical activity for cognitive and mental health in youth: a systematic review of mechanisms. Pediatrics. (2016) 138(3):e20161642. 10.1542/peds.2016-1642 PubMed DOI

Balke B, Ware RW. An experimental study of physical fitness of air force personnel. U S Armed Forces Med J. (1959) 10(6):675–88. PubMed

Guixeres J, Redon P, Saiz J, Alvarez J, Torro MI, Cantero L, et al. Cardiovascular fitness in youth: association with obesity and metabolic abnormalities. Nutr Hosp. (2014) 29(6):1290–7. 10.3305/nh.2014.29.6.7383 PubMed DOI

Ruiz JR, Castro-Pinero J, Espana-Romero V, Artero EG, Ortega FB, Cuenca MM, et al. Field-based fitness assessment in young people: the ALPHA health-related fitness test battery for children and adolescents. Br J Sports Med. (2011) 45(6):518–24. 10.1136/bjsm.2010.075341 PubMed DOI

Markert J, Herget S, Petroff D, Gausche R, Grimm A, Kiess W, et al. Telephone-based adiposity prevention for families with overweight children (T.A.F.F.-study): one year outcome of a randomized, controlled trial. Int J Environ Res Public Health. (2014) 11(10):10327–44. 10.3390/ijerph111010327 PubMed DOI PMC

Lison JF, Real-Montes JM, Torro I, Arguisuelas MD, Alvarez-Pitti J, Martinez-Gramage J, et al. Exercise intervention in childhood obesity: a randomized controlled trial comparing hospital-versus home-based groups. Acad Pediatr. (2012) 12(4):319–25. 10.1016/j.acap.2012.03.003 PubMed DOI

Bruño A, Escobar P, Cebolla A, Alvarez-Pitti J, Guixeres J, Lurbe E, et al. Home-exercise childhood obesity intervention: a randomized clinical trial comparing print versus web-based (move it) platforms. J Pediatr Nurs. (2018) 42:e79–84. 10.1016/j.pedn.2018.04.008 PubMed DOI

Paluchova V, Oseeva M, Brezinova M, Cajka T, Bardova K, Adamcova K, et al. Lipokine 5-PAHSA is regulated by adipose triglyceride lipase and primes adipocytes for de novo lipogenesis in mice. Diabetes. (2020) 69(3):300–12. 10.2337/db19-0494 PubMed DOI PMC

Sistilli G, Kalendova V, Cajka T, Irodenko I, Bardova K, Oseeva M, et al. Krill oil supplementation reduces exacerbated hepatic steatosis induced by thermoneutral housing in mice with diet-induced obesity. Nutrients. (2021) 13(2):437. 10.3390/nu13020437 PubMed DOI PMC

Go YM, Walker DI, Liang Y, Uppal K, Soltow QA, Tran V, et al. Reference standardization for mass spectrometry and high-resolution metabolomics applications to exposome research. Toxicol Sci. (2015) 148(2):531–43. 10.1093/toxsci/kfv198 PubMed DOI PMC

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NCT05907785