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.

Studies of physical activity behaviours have increasingly shown the importance of heritable factors such as genetic variation. Non-synonymous polymorphisms of alphaactinin 3 (ACTN3) and the β-adrenergic receptors 1 and 3 (ADRB) have been previously associated with exercise capacity and cardiometabolic health. We thus hypothesized that these polymorphisms are also related to physical activity behaviors in young adults. To test this hypothesis we examined relationships between ACTN3 (R577X), ARDB1 (Arg389Gly) and ADRB3 (Trp64Arg), and physical activity behaviors in university students. We stratified for student enrollment in kinesiology degree programs compared to non-majors as we previously found this to be a predictor of physical activity. We did not identify novel associations between physical activity and ACTN3. However, the minor alleles of ADRB1 and ADRB3 were significantly underrepresented in kinesiology students compared to non-majors. Furthermore, carriers of the ADRB1 minor allele reported reduced participation in moderate physical activity and increased afternoon fatigue compared to ancestral allele homozygotes. Together, these findings suggest that the heritability of physical activity behaviours in young adults may be linked to nonsynonymous polymorphisms within β-adrenergic receptors.

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Exercise‐related polymorphisms have played an important role in shaping human evolution. One such polymorphism, ACTN3 R577X, is overrepresented in endurance athletes and centenarians suggesting an association with favorable metabolic health. As such, we examined the influence of ACTN3 genotype on health‐related phenotypes in young subjects (age 18‐35) from the Assessing Inherent Markers for Metabolic syndrome in the Young (AIMMY) study (n=188). Cardiovascular, anthropometric, metabolic and body composition characteristics were assessed. ACTN3 genotype was associated with BMI in a sex specific manner, with null (XX) females having higher scores, while male positive (RR/RX) allele carriers had greater scores compared to XX males (p<0.05). Similarly, body fat percentage and waist circumference measurements were higher in females of the XX genotype compared to RR/RX allele carriers (p<0.05). In males, body circumferences and waist:hip ratio were higher in RR/RX allele carriers compared to XX individuals. Interestingly, Male RR/RX allele carriers had higher blood glucose and diastolic blood pressure than XX males. It was also found that female RR/RX carriers had higher VO2 peak scores than XX females (p<0.05). Metabolic and cardiovascular associations with ACTN3 genotype may offer novel insight into predicted athletic performance and disease risk.