Introduction
Athlete performance depends to some extent on skeletal muscle fiber-type composition, i.e. athletes practicing endurance sports usually have a higher proportion of slow-twitch type I fibers, while fast-twitch type II fibers are more common for athletes in explosive sports. Insulin sensitivity has also been correlated with proportion of type I fibers, i.e. insulin resistant individuals having reduced muscle oxidative capacity with less oxidative type I and more glycolytic type IIx fibers.
Aims
Here we aimed to identify genetic variation and corresponding biological mechanisms affecting human skeletal muscle histology.
Methods
We performed a genome-wide association meta-analysis in Swedish males from 3 independent cohorts (n=656) with skeletal muscle histological phenotypes, e.g. capillary density, fibre-type distribution and area (measured by ATPas staining). Skeletal muscle microarray expression data (n=77) were used for an eQTL analysis of associated markers. Follow-up of capillary density was done in Swedish elite cross-country skiers (n=15).
Results
We identified 11 genome-wide significant (p<5x10-8) independent loci (STEAP, NYAP2, ADRA1B, TNFSF11, FAM155A, SLC22A10, FASLG, RBFOX1, FOXJ2, KCNMA1, RAB3GAP2) associated with 6 skeletal muscle phenotypes. eQTL-genes corresponding to the top associated variants were enriched in metabolic pathways. Using a population differentiation neutrality test we show that some of the fibre-type nominally associated loci (p<1x10-6) fall within regions of positive selection (i.e. FHIT, CRISP and ANXA1). The G-allele of rs115660502 (MAF=0.048) was significantly associated (p=2x10-8) with increased capillary density and also decreased expression of the nearby gene RAB3GAP2 (FDR=0.007). The G-allele also had a significantly higher frequency (MAF=0.122, p=0.029) in the cohort of Swedish elite skiers.
Conclusion
Our results add to our understanding of skeletal muscle architecture and indicate that there is a genetic component to it and that this might contribute to increased endurance performance in sport athletes.
2015.