N-Lactoyl amino acids as metabolic biomarkers differentiating low and high exercise response

Maha Sellami; Khaled Naja; Shamma Almuraikhy; Najeha Anwardeen; Rinat Sultanov; Eduard Generozov; Ildus Ahmetov; Mohamed Elrayess

doi:10.5114/biolsport.2025.145912

eISSN: 2083-1862
ISSN: 0860-021X

Biology of Sport

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abstract:

Original paper

N-Lactoyl amino acids as metabolic biomarkers differentiating low and high exercise response

Maha Sellami

¹

,

Khaled Naja

²

,

Shamma Almuraikhy

²

,

Najeha Anwardeen

²

,

Rinat I. Sultanov

³

,

Eduard V. Generozov

³

,

Ildus I. Ahmetov

^{3, 4, 5}

,

Mohamed A. Elrayess

^{2, 6}

Physical Education Department (PE), College of Education, Qatar University, Doha, Qatar
Biomedical Research Center, Qatar University, Doha P.O Box 2713, Qatar
Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia
Laboratory of Genetics of Aging and Longevity, Kazan State Medical University, Kazan, Russia
Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK
College of Medicine, QU Health, Qatar University, Doha P.O Box 2713, Qatar

Biol Sport. 2025;42(2):331–344

DOI: https://doi.org/10.5114/biolsport.2025.145912

Online publish date: 2024/12/19

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Aerobic physical exercise has significant benefits for cardiovascular health; however, some individuals experience no benefit or even adverse effects. One reason for poor tolerance to aerobic exercise may be a low percentage of slow-twitch (oxidative) muscle fibers. This study aims to identify the metabolic signatures associated with low and high response to exercise by comparing the metabolic profiles of participants categorized according to their improvement of the 6-minute walking distance. In this study, pre- and post exercise intervention measurements of the 6-minute walking distance were conducted in forty-three lean and overweight young women, followed by non-targeted metabolomics analysis of 1039 known metabolites. An independent validation cohort comprising 791 individuals from the GTEx project was used to assess the gene expression of selected targets. The results indicated that a low improvement in the 6-minute walking distance (Δ 6-MWD = 27 meters) was associated with higher serum levels of N-lactoyl amino acid metabolites, particularly the exercise-inducible metabolite N-lactoyl phenylalanine (Lac-Phe) (FDR = 0.016), compared to high responders. Our results were corroborated in an independent validation cohort, which showed that the gene expression of cytosolic nonspecific dipeptidase (CNDP2), the enzyme responsible for Lac-Phe synthesis, is negatively associated with the percentage of slow-twitch muscle fibers (p < 0.0001). N-lactoyl amino acids may serve as biomarkers for rapid muscle fatigue and low response to exercise, and could be used as metabolic indicators to differentiate exercise response efficacy.

keywords:

N-Lactoyl amino acids as metabolic biomarkers differentiating low and high exercise response

Maha Sellami 1 , Khaled Naja 2 , Shamma Almuraikhy 2 , Najeha Anwardeen 2 , Rinat I. Sultanov 3 , Eduard V. Generozov 3 , Ildus I. Ahmetov 3, 4, 5 , Mohamed A. Elrayess 2, 6

N-lactoyl amino acids, Phe-Lac, Biomarkers, Metabolomics, Exercise response, 6-minutes walking test

Maha Sellami

¹

,

Khaled Naja

²

,

Shamma Almuraikhy

²

,

Najeha Anwardeen

²

,

Rinat I. Sultanov

³

,

Eduard V. Generozov

³

,

Ildus I. Ahmetov

^{3, 4, 5}

,

Mohamed A. Elrayess

^{2, 6}