Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention.

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

The stiffness response of type IIa fibres after eccentric exercise-induced muscle damage is dependent on ACTN3 r577X polymorphism.

The aim of the study was to determine the effect of α-actinin-3 (ACTN3) deficiency (XX) on muscle damage induced by an eccentric exercise bout. In this purpose, 4 RR and 4 XX individuals performed an intensive eccentric knee flexion exercise on an isokinetic dynamometer. Muscle biopsies, blood and pain scores were taken before and after the exercise to determine the extent of the exercise-induced damage and the effect of the ACTN3 R577X polymorphism. Maximal isometric strength of the quadriceps and single fibre properties were compared before and after the exercise. The drop in maximal isometric strength of the quadriceps at 45° knee flexion following the eccentric exercise bout was on average 37% 24 h post-exercise. The decrease in force was also apparent in isolated type IIa fibres (8%; P = 0.02), but not in type I fibres (P = 0.88). Creatine kinase and myoglobin plasma levels increased in all participants at least by 55% and 87%, respectively (P < 0.05). In addition, mRNA levels of markers for muscle regeneration and muscle remodelling increased after the eccentric exercise (P < 0.05), however, independently from ACTN3 R577X genotype. The mRNA level of nuclear factor of activated T-cells 1 (NFATc1) decreased after the eccentric exercise only in XX genotypes (P < 0.05). The stiffness of type IIa, but not type I muscle fibres increased only in RR individuals after the eccentric exercise (P < 0.05). While no major effect of α-actinin-3 deficiency on susceptibility to muscle damage was found acutely, the increased stiffness response in fast RR fibres might be a protection mechanism from muscle damage during a subsequent eccentric exercise bout.

Evidence for ACTN3 as a Speed Gene in Isolated Human Muscle Fibers.

PURPOSE: To examine the effect of α-actinin-3 deficiency due to homozygosity for the ACTN3 577X-allele on contractile and morphological properties of fast muscle fibers in non-athletic young men. METHODS: A biopsy was taken from the vastus lateralis of 4 RR and 4 XX individuals to test for differences in morphologic and contractile properties of single muscle fibers. The cross-sectional area of the fiber and muscle fiber composition was determined using standard immunohistochemistry analyses. Skinned single muscle fibers were subjected to active tests to determine peak normalized force (P0), maximal unloading velocity (V0) and peak power. A passive stretch test was performed to calculate Young's Modulus and hysteresis to assess fiber visco-elasticity. RESULTS: No differences were found in muscle fiber composition. The cross-sectional area of type IIa and IIx fibers was larger in RR compared to XX individuals (P<0.001). P0 was similar in both groups over all fiber types. A higher V0 was observed in type IIa fibers of RR genotypes (P<0.001) but not in type I fibers. The visco-elasticity as determined by Young's Modulus and hysteresis was unaffected by fiber type or genotype. CONCLUSION: The greater V0 and the larger fast fiber CSA in RR compared to XX genotypes likely contribute to enhanced whole muscle performance during high velocity contractions.

History-dependent force, angular velocity and muscular endurance in ACTN3 genotypes.

PURPOSE: This study aimed at determining the influence of the ACTN3 R577X polymorphism on muscle strength and muscle endurance in non-athletic young men. METHODS: 266 healthy young men were included in this study. Each subject performed maximal isometric, concentric and eccentric contractions of the knee extensor muscles on an isokinetic dynamometer. Force depression, force enhancement and the fatigue index were derived from these data. In addition, handgrip strength, squat jump (SJ) and counter movement jump (CMJ) height were obtained. RESULTS: Our group included 83 RR (31 %), 131 RX (49 %) and 52 XX (20 %) individuals. The muscle bone cross-sectional area of the thigh was 5 % higher in RR compared to XX individuals (P = 0.033). RR genotypes showed 6 % higher handgrip strength compared to the XX group (P = 0.047). They also jumped 5 % higher in both the SJ and CMJ tests (P = 0.029; P = 0.031). No differences were found in force depression, force enhancement, isometric or eccentric strength. The relative concentric knee torque at 200°/s and at 300°/s was 7 and 8 % higher in RR compared to XX genotypes, respectively (P = 0.049; P = 0.048). Also, the fatigue index was found to be 4 % lower in XX genotypes (P = 0.037). CONCLUSIONS: Our findings are in agreement with the higher prevalence of the RR genotype in power-oriented activities. The better fatigue index of XX genotypes may be beneficial in endurance-type activities.

A genetic predisposition score associates with reduced aerobic capacity in response to acute normobaric hypoxia in lowlanders.

Given the high inter-individual variability in the sensitivity to high altitude, we hypothesize the presence of underlying genetic factors. The aim of this study was to construct a genetic predisposition score based on previously identified high-altitude gene variants to explain the inter-individual variation in the reduced maximal O2 uptake (ΔVo2max) in response to acute hypoxia. Ninety-six healthy young male Belgian lowlanders were included. In both normobaric normoxia (Fio2=20.9%) and acute normobaric hypoxia (Fio2=10.7%-12.5%) Vo2max was measured. Forty-one SNPs in 21 genes were genotyped. A stepwise regression analysis was applied to detect a subset of SNPs to be associated with ΔVo2max. This subset of SNPs was included in the genetic predisposition score. A general linear model and regression analysis with age, weight, height, hypoxic protocol group, and Vo2max in normoxia as covariates were used to test the explained variance of the genetic predisposition score. A ROC analysis was performed to discriminate between the low- and high ΔVo2max subgroups. A stepwise regression analysis revealed a subset of SNPs [rs833070 (VEGFA), rs4253778 (PPARA), rs6735530 (EPAS1), rs4341 (ACE), rs1042713 (ADRB2), and rs1042714 (ADRB2)] to be associated with ΔVo2max. The genetic predisposition score was found to be an independent predictive variable with a partial explained variance of 23% (p<0.0001). A ROC analysis showed significant discriminating accuracy (AUC=0.78, 95% confidence interval=0.64-0.91) between the low- and high ΔVo2max subgroups. This six-SNP based genetic predisposition score showed a significantly predictive value for ΔVo2max.

Role of alpha-actinin-3 in contractile properties of human single muscle fibers: a case series study in paraplegics.

A common nonsense polymorphism in the ACTN3 gene results in the absence of α-actinin-3 in XX individuals. The wild type allele has been associated with power athlete status and an increased force output in numeral studies, though the mechanisms by which these effects occur are unclear. Recent findings in the Actn3(-/-) (KO) mouse suggest a shift towards 'slow' metabolic and contractile characteristics of fast muscle fibers lacking α-actinin-3. Skinned single fibers from the quadriceps muscle of three men with spinal cord injury (SCI) were tested regarding peak force, unloaded shortening velocity, force-velocity relationship, passive tension and calcium sensitivity. The SCI condition induces an 'equal environment condition' what makes these subjects ideal to study the role of α-actinin-3 on fiber type expression and single muscle fiber contractile properties. Genotyping for ACTN3 revealed that the three subjects were XX, RX and RR carriers, respectively. The XX carrier's biopsy was the only one that presented type I fibers with a complete lack of type II(x) fibers. Properties of hybrid type II(a)/II(x) fibers were compared between the three subjects. Absence of α-actinin-3 resulted in less stiff type II(a)/II(x) fibers. The heterozygote (RX) exhibited the highest fiber diameter (0.121±0.005 mm) and CSA (0.012±0.001 mm(2)) and, as a consequence, the highest peak force (2.11±0.14 mN). Normalized peak force was similar in all three subjects (P = 0.75). Unloaded shortening velocity was highest in R-allele carriers (P<0.001). No difference was found in calcium sensitivity. The preservation of type I fibers and the absence of type II(x) fibers in the XX individual indicate a restricted transformation of the muscle fiber composition to type II fibers in response to long-term muscle disuse. Lack of α-actinin-3 may decrease unloaded shortening velocity and increase fiber elasticity.