Abstract
Homozygosity for a premature stop codon (X) in the ACTN3 “sprinter” gene is common in humans despite the fact that it reduces muscle size, strength and power. Because of the close relationship between skeletal muscle function and cardiometabolic health we examined the influence of ACTN3 R577X polymorphism over cardiovascular and metabolic characteristics of young adults (n = 98 males, n = 102 females; 23 ± 4.2 years) from our Assessing Inherent Markers for Metabolic syndrome in the Young (AIMMY) study. Both males and females with the RR vs XX genotype achieved higher mean VO2 peak scores (47.8 ± 1.5 vs 43.2 ±1.8 ml/O2/min, p = 0.002) and exhibited higher resting systolic (115 ± 2 vs 105 ± mmHg, p = 0.027) and diastolic (69 ± 3 vs 59 ± 3 mmHg, p = 0.005) blood pressure suggesting a role for ACTN3 in the maintenance of vascular tone. We subsequently identified the expression of alpha-actinin 3 protein in pulmonary artery smooth muscle, which may explain the genotype-specific differences in cardiovascular adaptation to acute exercise. In addition, we utilized targeted serum metabolomics to distinguish between RR and XX genotypes, suggesting an additional role for the ACTN3 R577X polymorphism in human metabolism. Taken together, these results identify significant cardiometabolic effects associated with possessing one or more functional copies of the ACTN3 gene.
Highlights
The sarcomeric α-actinins play an important role in generating skeletal muscle contractions by stabilizing actin thin filaments within the myofibrillar array [1, 2]
As a means of ensuring genotyping accuracy we analyzed our AIMMY cohort and found the ACTN3 R577X locus to be in Hardy-Weinberg Equilibrium (HWE) (Table 1) with (p(R) = 0.558; p(X) = 0.442; P = 0.54) as described previously [28]
Whereas the ACTN3 R577X polymorphism has been associated with muscle performance phenotypes in elite and amateur power athletes, studies linking it to cardiometabolic fitness are challenged by a lack of mechanistic evidence [5]
Summary
The sarcomeric α-actinins play an important role in generating skeletal muscle contractions by stabilizing actin thin filaments within the myofibrillar array [1, 2]. In human skeletal muscle αactinin-2 (encoded by the ACTN2 gene) is expressed in all muscle fiber types whereas α-actinin-3 (ACTN3) is expressed in a subset of fast-twitch glycolytic muscle fibers where it contributes to the generation of rapid contractions [1]. PLOS ONE | DOI:10.1371/journal.pone.0130644 June 24, 2015
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