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

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) and found that the rs115660502 G allele was associated 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. 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. 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.