Background: Emerging research supports that exercise positively affects neurodevelopment. However, the mechanisms linking exercise with brain health are largely unknown. We aimed to investigate the effect of exercise on (i) blood biomarkers selected based on previous evidence (Brain-derived neurotrophic factor (BDNF), Beta-hydroxybutyrate (BHB), Cathepsin B (CTSB), Kynurenine, Fibroblast growth factor 21 (FGF21), Vascular cell adhesion molecule-1 (sVCAM-1)); and (ii) a panel of 92 neurology-related proteins (discovery analysis). We also investigated whether changes in these biomarkers mediate the effects of exercise on brain health (hippocampal structure and function, cognitive performance, and mental health). Methods: 81 children with overweight/obesity (41% girls) were randomized to either 20-week of aerobic plus resistance exercise or control. Candidate biomarkers were assessed using ELISA for Kynurenine, FGF21, and CTSB, colorimetry for BHB, and XMap for BDNF and VCAM-1. The 92 neurology-related proteins were analyzed by antibody-based proteomic analyses. Results: Our intervention had no significant effect on candidate biomarkers (all p>0.05). In the discovery analysis, a reduction in circulating macrophage scavenger receptor type-I (MSR1) was observed (standardized differences between groups (SMD): -0.3, p=0.001). This effect was validated using ELISA methods (SMD: -0.3, p=0.01). None of the biomarkers mediated the effects of exercise on brain health. Conclusions: Our study does not support a chronic effect of exercise on candidate biomarkers. Nevertheless, we observed that chronic exercise reduced the levels of MRS1, while it did not mediate the effects of exercise on brain health. Future studies should explore the implications of this novel biomarker on general health.

The authors have declared no competing interest.

NCT02295072

This work study was mainly supported by the Spanish Ministry of Economy and Competitiveness (DEP2017-91544-EXP) and the Alicia Koplowitz Foundation. This study was also supported by grants from the Spanish Ministry of Economy and Competitiveness (DEP2013-47540, DEP2016-79512-R), European Regional Development Fund (ERDF), and by the European Commission(No 667302). Additional funding was obtained from the Andalusian Operational Programme supported with ERDF (FEDER in Spanish, B-CTS-355-UGR18, B-CTS-500-UGR18 and ACTS-614-UGR20). This study was partially funded by the University of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES) and by the Junta de Andalucia, Consejeria de Conocimiento, Investigacion y Universidades and ERDF (SOMM17/6107/UGR). In addition, this study was further supported by the SAMID III network, RETICS, funded by the PN I+D+I 2017-2021 (Spain). MRA is funded by the Ramon Areces Foundation, DEP2017-91544-EXP, the Alicia Koplowitz Foundation (ALICIAK-2018). AMG with FPU16/ 03653. IEC is supported by the Spanish Ministry of Science and Innovation (RYC2019-027287-I). PSU is supported by a grant from ANID/BECAS Chile/72180543 and through a Margarita Salas grant from the Spanish Ministry Universities. SA is supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER): grants RYC- 2016- 21199 and SAF2017-87526-R, and the Junta de Andalucia (PAIDI P20_00158). APF is supported by the Spanish Ministry of Education, Culture and Sport (FPU 16/02760).

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The ActiveBrains project was approved by the Human Research Ethics Committee of the University of Granada. Additionally, it was registered in ClinicalTrials.gov (identifier: NCT02295072).The parents or legal guardians signed an informed consent to participate in the study.

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All data produced in the present study are available upon reasonable request to the authors