RAB3GAP2 is a regulator of skeletal muscle endothelial cell proliferation and associated with capillary-to-fiber ratio

Skeletal muscle capillary density is correlated with physical performance and whole-body metabolic properties. Thus, we performed a genome-wide association study of skeletal muscle capillary-to-fiber ratio (C:F) (n = 603 males) and found that the rs115660502 G allele was associated (p < 5 × 10<sup>-8</sup>) with increased C:F and reduced skeletal muscle expression of RAB3 GTPase-activating non-catalytic protein subunit 2 (RAB3GAP2). The capillary-increasing G allele was more prevalent in elite endurance athletes than in power athletes and non-athlete controls in two independent cohorts. Low-muscle-expressing RAB3GAP2 expression quantitative trait locus (eQTL) alleles were associated with muscle damage in athletes. In healthy individuals, RAB3GAP2 expression was reduced by high-intensity intermittent training. RAB3GAP2 protein was not uniformly expressed in muscle but predominantly expressed in the endothelium and capillaries. RAB3GAP2 expression was lower in endurance compared with power athletes and was negatively associated with type I (oxidative) muscle fiber density. Experimental reduction of RAB3GAP2 in human endothelial cells led to (1) increased proliferation and tube formation in vitro, (2) regulation of secreted factors (e.g., CD70 and TNC) promoting angiogenesis and T cell activation, and (3) increased in vivo endothelial cell density in mice. RAB3GAP2 expression in skeletal muscle was negatively correlated with exercise-induced release of TNC in vivo in humans. In conclusion, RAB3GAP2 is expressed in the microvascular endothelium and is suggested to be a negative regulator of angiogenesis through a decrease in endothelial cell proliferation, possibly mediated by RAB18, with its low-expressing variant associated with higher muscle C:F and elite endurance performance.

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Journal
Cell Reports
Published
2026-02-01
DOI
https://doi.org/10.1016/j.celrep.2026.116961
Primary Topic
Genetics and Physical Performance
Type
article
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0.00

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article

RAB3GAP2 is a regulator of skeletal muscle endothelial cell proliferation and associated with capillary-to-fiber ratio

Andrey K. Larin, Johan Andersson, Konstantin Babalyan, Manonanthini Thangam et al.
Cell Reports
Genetics and Physical Performance
article

RAB3GAP2 is a regulator of skeletal muscle endothelial cell proliferation and associated with capillary-to-fiber ratio

Andrey K. Larin, Johan Andersson, Konstantin Babalyan, Manonanthini Thangam, Ekaterina A. Semenova, Nikolay A. Kulemin, Dmytro Kryvokhyzha, Kristoffer Ström, Mikko Lehtovirta, Ola Ekström, Kerry McGawley, Steven Reid, Emma Ahlqvist, Bilal Ahmad Mir, Noriyuki Fuku, Adam Jacek Kretowski, Łukasz Szczerbiński, Edward V. Generozov, Kristian Pietras, Sebastian Kalamajski, Motoyuki Iemitsu, Nikolay Oskolkov, Ellen Kakulidis, Abbas Dehghan, Anna-Maria Dutius Andersson, Karl-Fredrik Eriksson, Maria Fernandez Gomez, Hans-Christer Holmberg, Hugo Zeberg, Yannis Pitsiladis, Joao Fadista, Anubha Mahajan, Alejandro Lucia, Kay Prüfer, Rashmi B. Prasad, Michael Hultström, Andrew P. Morris, Rinat I. Sultanov, Nicholas L. Smith, Enming Zhang, Guan Wang, Ildus I. Ahmetov, Lars Lind, Cecilia M. Lindgren, Anders Larsson, Andrey V. Zhelankin, Miklos Lipcsey, Paul W. Franks, Eri Miyamoto-Mikami, Ola Hansson, Alejandro Santos-Lozano, Claes Ladenvall
article en

Abstract

Skeletal muscle capillary density is correlated with physical performance and whole-body metabolic properties. Thus, we performed a genome-wide association study of skeletal muscle capillary-to-fiber ratio (C:F) (n = 603 males) and found that the rs115660502 G allele was associated (p < 5 × 10<sup>-8</sup>) with increased C:F and reduced skeletal muscle expression of RAB3 GTPase-activating non-catalytic protein subunit 2 (RAB3GAP2). The capillary-increasing G allele was more prevalent in elite endurance athletes than in power athletes and non-athlete controls in two independent cohorts. Low-muscle-expressing RAB3GAP2 expression quantitative trait locus (eQTL) alleles were associated with muscle damage in athletes. In healthy individuals, RAB3GAP2 expression was reduced by high-intensity intermittent training. RAB3GAP2 protein was not uniformly expressed in muscle but predominantly expressed in the endothelium and capillaries. RAB3GAP2 expression was lower in endurance compared with power athletes and was negatively associated with type I (oxidative) muscle fiber density. Experimental reduction of RAB3GAP2 in human endothelial cells led to (1) increased proliferation and tube formation in vitro, (2) regulation of secreted factors (e.g., CD70 and TNC) promoting angiogenesis and T cell activation, and (3) increased in vivo endothelial cell density in mice. RAB3GAP2 expression in skeletal muscle was negatively correlated with exercise-induced release of TNC in vivo in humans. In conclusion, RAB3GAP2 is expressed in the microvascular endothelium and is suggested to be a negative regulator of angiogenesis through a decrease in endothelial cell proliferation, possibly mediated by RAB18, with its low-expressing variant associated with higher muscle C:F and elite endurance performance.

Cell ReportsVol. 45(2)
Uppsala University (SE), Centre for Human Genetics (GB), Ritsumeikan University (JP), Medical University of Białystok (PL), Malmö University (SE), Lund University (SE), Luleå University of Technology (SE), Kazan Federal University (RU), Science for Life Laboratory (SE), Universidad Europea Miguel de Cervantes (ES), Karolinska Institutet (SE), Juntendo University (JP), University of Oxford (GB), Research Institute Hospital 12 de Octubre (ES), Kaiser Permanente Washington Health Research Institute (US), Medicon Village (SE), Centre for Biomedical Network Research on Rare Diseases (ES), Arthritis UK (GB), Max Planck Institute for Evolutionary Anthropology (DE), Federal Scientific Center of Physical Culture and Sports (RU), Institute for Molecular Medicine Finland (FI), Imperial College London (GB), Mid Sweden University (SE), Federal Medical-Biological Agency (RU), University of Brighton (GB)
American Diabetes Association, European Commission, Stiftelsen för Strategisk Forskning, Lunds Universitet, Hjärt-Lungfonden, Knut och Alice Wallenbergs Stiftelse, Novo Nordisk, Vetenskapsrådet, Russian Science Foundation, Svenska Läkaresällskapet, Science for Life Laboratory, Novo Nordisk Fonden, National Institutes of Health, Instituto de Salud Carlos III, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Common Fund
Openalex Percentile: Top 57%
Genetics and Physical Performance
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