An international team of researchers led by Lund University in Sweden has uncovered a genetic variant that profoundly influences the body’s ability to form new blood vessels within skeletal muscles—a mechanism central to physical endurance, metabolic health, and recovery processes. The landmark study identifies the gene RAB3GAP2 as a key regulator of capillary density in muscle tissue, shedding light on the molecular underpinnings that differentiate endurance athletes from sprinters and non-athletes alike.
Capillaries are the finest blood vessels that penetrate muscle fibers, ensuring an efficient supply of oxygen and nutrients while facilitating the removal of metabolic waste. This dense vascular network is a crucial determinant of muscular endurance and metabolic efficiency. The more capillaries a muscle has, the more proficient it is at sustaining prolonged activity, which is particularly advantageous in endurance sports. Conversely, athletes specializing in explosive power and speed often do not rely on this vascular abundance but focus instead on rapid energy delivery and muscle strength.
Starting with a cohort of over 600 Swedish participants, the researchers analyzed both muscle biopsies and genomic data to identify genetic variants associated with capillary numbers. They discovered a variant in the RAB3GAP2 gene that correlates with increased capillary density. Notably, this variant reduces the expression of a protein that acts as a molecular brake on angiogenesis—the formation of new blood vessels. Individuals carrying the variant produced less of this inhibitory protein, thereby facilitating a denser capillary network within their muscle fibers.
The implications of this finding are particularly striking when examining elite athletes. Swedish cross-country skiers, representative of high-endurance competitors, were found to carry this variant at approximately twice the frequency observed in non-athletic individuals. This disparity underlines a genetic predisposition that favors enhanced endurance capabilities, suggesting that the presence of this variant provides a physiological edge by optimizing oxygen delivery and metabolic waste clearance during sustained muscle activity.
To validate these findings, the team expanded their investigation to include top-tier athletes from six different countries across Europe, America, and Asia. Consistently, endurance athletes demonstrated a higher prevalence of the RAB3GAP2 variant, reinforcing its role in promoting vascular adaptations favoring prolonged aerobic exercise. In stark contrast, the variant was exceedingly rare—under 1%—among world-class sprinters from Jamaica, highlighting its specificity to endurance physiology rather than explosive athletic performance.
Beyond genetic predisposition, the study revealed a fascinating facet of environmental influence. Through controlled high-intensity interval training (HIIT), the researchers demonstrated that the activity of the RAB3GAP2 protein brake could be modulated. HIIT sessions were shown to downregulate this protein’s function, effectively releasing the molecular brake and promoting angiogenesis within skeletal muscle. This adaptation underscores the vital role of exercise as a means of inducing vascular plasticity, thereby enhancing oxygen transport capacity and metabolic efficiency, regardless of one’s genetic makeup.
However, the power of this genetic variant and its associated protein regulation comes with inherent trade-offs. The researchers observed that the accelerated vascular growth linked to the low brake activity variant also correlated with heightened inflammatory responses and an increased susceptibility to muscle injury under certain conditions. This dual-edged effect illustrates the complexity of physiological adaptation, where the benefits of improved endurance must be balanced against the risks of tissue damage and impaired recovery.
The protein regulated by RAB3GAP2 functions analogously to a volume control knob for the body’s cellular stress response related to muscle remodeling. Athletes and individuals possessing the variant essentially start with this volume set higher, which amplifies the positive effects of training stimuli but requires careful management to avoid overtraining and injury. As training volume increases, so does the risk of surpassing the optimal window for recovery, revealing the delicate interplay between genetic potential and environmental demands.
These insights carry pioneering implications for sports science and medicine. Understanding the molecular pathways governing muscle capillarization and adaptation opens avenues for personalized training regimens tailored to an individual’s genetic profile. Such precision approaches could maximize athletic performance while mitigating injury risks. Furthermore, this knowledge extends to rehabilitation strategies, where modulating vascular growth could expedite recovery from muscular injuries or degenerative conditions.
Perhaps most exciting is the potential translational impact on metabolic disorders such as insulin resistance and type 2 diabetes. The researchers have initiated collaboration with pharmaceutical entities, including AstraZeneca, aiming to develop drugs that mimic the effect of releasing the vascular brake protein. Pharmacological inhibition of RAB3GAP2 could stimulate capillary growth in skeletal muscle, enhancing glucose uptake and offering a novel therapeutic strategy for combating metabolic disease—an area where current medical options remain limited.
In summary, this groundbreaking study elucidates a crucial genetic component behind muscular vascularization and its modulation through both inherent and external factors. By decoding the mechanisms of RAB3GAP2 and its role in endothelial cell proliferation within muscle, scientists are decoding how the human body tailors physical capacity, endurance, and metabolic health in response to genetics and training. This revelation marks a significant leap forward in understanding the intricate biological symphony underpinning athletic prowess and metabolic well-being.
Subject of Research: People
Article Title: RAB3GAP2 is a regulator of skeletal muscle endothelial cell proliferation and associated with capillary-to-fiber ratio
News Publication Date: 11-Feb-2026
Web References:
DOI: 10.1016/j.celrep.2026.116961
Image Credits: Åsa Hansdotter
Keywords: RAB3GAP2, capillary density, skeletal muscle, angiogenesis, endurance performance, high-intensity interval training, metabolic health, muscle vascularization, endothelial proliferation, genetic variation, sports genetics, muscle recovery
