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. 2025 Jul 28.
doi: 10.1007/s40279-025-02279-2. Online ahead of print.

Erythrocyte Glycolytic and Redox Metabolism Affects Muscle Oxygenation and Exercise Performance: A Randomized Double-Blind Crossover Study in Men

Panagiotis N Chatzinikolaou  1 , Nikos V Margaritelis  1 , Vassilis Paschalis  2 , Anastasios A Theodorou  3 , Eleni Moushi  3 , Ioannis S Vrabas  1 , Antonios Kyparos  1 , Ioannis G Fatouros  4 , Angelo D'Alessandro  5 , Michalis G Nikolaidis  6
Affiliations

Erythrocyte Glycolytic and Redox Metabolism Affects Muscle Oxygenation and Exercise Performance: A Randomized Double-Blind Crossover Study in Men

Panagiotis N Chatzinikolaou et al. Sports Med. .

Abstract

Background: Erythrocytes are traditionally considered passive oxygen carriers, yet their energetic and redox metabolism plays a critical role in regulating oxygen kinetics.

Objective: This study integrates experimental and computational data to provide a comprehensive analysis of erythrocyte metabolism in response to exercise-induced oxidative stress.

Methods: The study consisted of three phases: in vivo, ex vivo, and computational. A total of 20 male participants underwent a randomized crossover experiment with two conditions: oxidative stress (eccentric contractions) and control. Oxidative stress was induced via leg eccentric contractions, and its effects on erythrocyte glycolytic and redox metabolism, arm muscle oxygenation, and arm exercise performance were evaluated. The study protocol was preregistered on the Open Science Framework ( https://osf.io/ub6zs ).

Results: Eccentric contractions altered oxidative stress markers in erythrocytes (+ 22% F2-isoprostanes, + 28% protein carbonyls, - 20% glutathione). Oxidative stress increased erythrocyte glycolytic flux by + 53%, while arm exercise further increased glycolytic flux in both control (+ 200%) and oxidative stress (+ 86%) conditions. Exogenous hydrogen peroxide administration reduced glycolytic flux by - 48%. Stoichiometric analysis revealed that during acute exercise, erythrocytes produced 14.9% less ATP, NADPH, and 2,3-bisphosphoglycerate than their theoretical maximum, at the critical bioenergetic point. Oxidative stress decreased arm deoxygenated hemoglobin by - 7.4% during arm exercise and VO2peak by - 4% during arm exercise.

Conclusion: In a comprehensive exercise study investigating mechanistic relationships in erythrocyte biology, we show that erythrocyte metabolism (1) responds dynamically to exercise, (2) becomes dysregulated under oxidative stress, and (3) may partly influence muscle oxygenation and performance.

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Conflict of interest statement

Declarations. Funding: P.N.C. received financial support from the Special Account for Research Funds, Aristotle University of Thessaloniki (#630972), for the completion of his doctoral studies. Conflict of Interest: The authors have no conflicts of interest to declare that are relevant to the content of this article. Ethics Approval: The study was approved by the Ethics Committee of the Department of Physical Education and Sports Science at Serres (ERC-017/2022). The study protocol was also preregistered on the Open Science Framework ( https://osf.io/ub6zs ). Consent to Participate: Participants provided written informed consent, and all procedures conformed to the guidance presented by the Declaration of Helsinki. Consent for Publication: Not applicable. Availability of Data and Material: The data that support the findings of this study are openly available on GitHub: https://github.com/PanosChatzi/erythrocyte_study_statistical_analyses Code Availability: The code that supports the findings of this study are openly available on GitHub: https://github.com/PanosChatzi/erythrocyte_study_statistical_analyses ; https://github.com/PanosChatzi/erythrocyte-oxygen-metabolism . Authors’ Contributions: All authors have read and approved the final submitted manuscript and agree to be accountable for the work. P.N.C.: conceptualization; writing—original draft; writing—review and editing; data collection; statistics; analysis; visualization; software. N.V.M.: data curation; statistics; writing—original draft; writing—review and editing. V.P.: data curation; writing—original draft; writing—review and editing. A.A.T.: data collection; writing—original draft; writing—review and editing; E.M.: data collection; writing—review and editing. I.S.V.: writing—original draft; writing—review and editing. A.K.: writing—original draft; writing—review and editing. IGF: writing—original draft; writing—review and editing. A.D.: writing—original draft; writing—review and editing. M.G.N.: conceptualization; supervision; project administration; writing—original draft; writing—review and editing.

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