EPAS1 is associated with human muscle fiber composition and endurance phenotypes

Dautova, AZ, Valeeva, EV, Semenova, EA, Mavliev, FA, Zverev, AA, Nazarenko, AS, John, G, Zhelankin, AV ORCID: 0000-0002-3014-2005, Larin, AK, Kulemin, NA, Sultanov, RI, Generozov, EV and Ahmetov, II ORCID: 0000-0002-6335-4020 (2026) EPAS1 is associated with human muscle fiber composition and endurance phenotypes. Physiological Reports, 14 (10). pp. 1-16. ISSN 2051-817X

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Abstract

A recent study reported that endothelial PAS domain protein 1 (EPAS1; hypoxia-inducible factor 2α) acts downstream of PGC-1α to regulate the slow-twitch muscle fiber program in mice, yet its role in human physiology and exercise adaptation remains unclear. The aim of this study was threefold: (1) to investigate EPAS1 gene expression in human skeletal muscle and its association with muscle fiber composition and the expression of endurance-related genes; (2) to determine how EPAS1 expression responds to aerobic training; and (3) to examine whether EPAS1 genetic variation is linked to aerobic capacity, hemoglobin, and athletic status. The study involved 1234 subjects, including 943 athletes and 291 untrained individuals. EPAS1 gene expression was significantly higher in endurance athletes compared with power athletes (p = 0.011) and was positively associated with the proportion of slow-twitch muscle fibers in the vastus lateralis of untrained subjects (p = 0.0008) and athletes (p = 0.0033). EPAS1 expression was higher in females (p = 0.0028) and negatively associated with smoking status (p = 0.0007). Moreover, EPAS1 expression showed positive association with endurance-related genes, including ANGPT2, CKM, CPT1B, EPOR, FNDC5, HIF1A, KDR, MYBPC3, NFATC4, NOS3, PPARA, PPARD, PPARGC1A, UCP2, and VEGFA. Analysis of 24 publicly available skeletal muscle transcriptomic datasets demonstrated that EPAS1 expression increased significantly (meta-analysis p = 9.2 × 10−5) following aerobic training. Finally, genetically predicted higher EPAS1 expression (i.e., carriage of the EPAS1 rs6756667 A allele) was positively associated with endurance athlete status in both sexes (p = 0.0004) and with VO₂max (p = 0.046) and hemoglobin (p = 0.041) in male athletes. These findings potentially identify EPAS1 as an important genetic factor associated with muscle fiber composition, endurance-related phenotypes, and adaptation to aerobic training.

Item Type:	Article
Uncontrolled Keywords:	aerobic performance; athletic performance; genotype; muscle; polymorphism; talent; Muscle Fibers, Slow-Twitch; Humans; Exercise; Physical Endurance; Phenotype; Adult; Female; Male; Muscle Fibers, Skeletal; Young Adult; Athletes; Basic Helix-Loop-Helix Proteins; Endothelial PAS Domain-Containing Protein 1; aerobic performance; athletic performance; genotype; muscle; polymorphism; talent; Humans; Female; Endothelial PAS Domain-Containing Protein 1; Basic Helix-Loop-Helix Proteins; Male; Physical Endurance; Phenotype; Adult; Muscle Fibers, Skeletal; Muscle Fibers, Slow-Twitch; Athletes; Young Adult; Exercise; 3208 Medical Physiology; 32 Biomedical and Clinical Sciences; Genetics; Human Genome; Clinical Research; 2.1 Biological and endogenous factors; Musculoskeletal; Humans; Male; Female; Basic Helix-Loop-Helix Proteins; Physical Endurance; Adult; Young Adult; Phenotype; Muscle Fibers, Skeletal; Athletes; Muscle Fibers, Slow-Twitch; Exercise; Polymorphism, Single Nucleotide; 0606 Physiology; 1103 Clinical Sciences; 1116 Medical Physiology; 3208 Medical physiology
Subjects:	Q Science > QP Physiology R Medicine > RC Internal medicine > RC1200 Sports Medicine
Divisions:	Sport and Exercise Sciences
Publisher:	Wiley
Date of acceptance:	12 May 2026
Date of first compliant Open Access:	9 July 2026
Date Deposited:	09 Jul 2026 15:06
Last Modified:	09 Jul 2026 15:06
DOI or ID number:	10.14814/phy2.70928
URI:	https://researchonline.ljmu.ac.uk/id/eprint/28987

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