Olaf Holz,1,* David S DeLuca,2,* Stefan Roepcke,3 Thomas Illig,2 Klaus M Weinberger,46 Christian Schudt,7 Jens M Hohlfeld1,2

1Fraunhofer ITEM, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover, Germany; 2Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover, Germany; 3Department of Biomarker Development, Takeda Pharmaceuticals International GmbH, Zrich, Switzerland; 4Biocrates Life Sciences AG, Innsbruck, Austria; 5Research Group for Clinical Bioinformatics, Private University for Health Sciences, Medical Informatics and Technology, Hall in Tirol, Austria; 6sAnalytiCo Ltd, Belfast, Ireland; 7Department of Biochemistry, ALTANA, Konstanz, Germany

*These authors contributed equally to this work

Correspondence: Olaf HolzDepartment of Clinical Airway Research, Fraunhofer ITEM, Hannover 30625, GermanyTel +49-511-5350-8141Fax +49-511-5350-8250Email olaf.holz@item.fraunhofer.de

Purpose: There is an ongoing demand for easily accessible biomarkers that reflect the physiological and pathophysiological mechanisms of COPD. To test if an exercise challenge could help to identify clinically relevant metabolic biomarkers in COPD.Patients and Methods: We performed two constant-load exercise challenges separated by 4 weeks including smokers with COPD (n=23/19) and sex- and age-matched healthy smokers (n=23/20). Two hours after a standardized meal venous blood samples were obtained before, 5 mins after the start, at the end of submaximal exercise, and following a recovery of 20 mins. Data analysis was performed using mixed- effects model, with the metabolite level as a function of disease, time point and interaction terms and using each individuals resting level as reference.Results: Exercise duration was longer in healthy smokers but lactate levels were comparable between groups at all four time points. Glucose levels were increased in COPD. Glutamine was lower, while glutamate and arginine were higher in COPD. Branched-chain amino acids showed a stronger decline during exercise in healthy smokers. Carnitine and the acyl-carnitines C16 and C18:1 were increased in COPD. These metabolite levels and changes were reproducible in the second challenge.Conclusion: Higher serum glucose, evidence for impaired utilization of amino acids during exercise and a shift of energy metabolism to enhanced consumption of lipids could be early signs for a developing metabolic syndrome in COPD. In COPD patients, deviations of energy and nitrogen metabolism are amplified by an exercise challenge.

Keywords: targeted metabolomics, biomarker, airway inflammation

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