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Alejandro Lucia - One of the best experts on this subject based on the ideXlab platform.
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ACTN3 r577x genotype and exercise phenotypes in recreational marathon runners
Genes, 2019Co-Authors: Juan Del Coso, Beatriz Lara, Victor Moreno, Jorge Gutierrezhellin, Gabriel Baltazarmartins, Carlos Ruizmoreno, Millan Aguilarnavarro, Alejandro LuciaAbstract:Background: Homozygosity for the X-allele in the ACTN3 R577X (rs1815739) polymorphism results in the complete absence of α-actinin-3 in sarcomeres of fast-type muscle fibers. In elite athletes, the ACTN3 XX genotype has been related to inferior performance in speed and power-oriented sports; however, its influence on exercise phenotypes in recreational athletes has received less attention. We sought to determine the influence of ACTN3 genotypes on common exercise phenotypes in recreational marathon runners. Methods: A total of 136 marathoners (116 men and 20 women) were subjected to laboratory testing that included measurements of body composition, isometric muscle force, muscle flexibility, ankle dorsiflexion, and the energy cost of running. ACTN3 genotyping was performed using TaqMan probes. Results: 37 runners (27.2%) had the RR genotype, 67 (49.3%) were RX and 32 (23.5%) were XX. There was a difference in body fat percentage between RR and XX genotype groups (15.7 ± 5.8 vs. 18.8 ± 5.5%; effect size, ES, = 0.5 ± 0.4, p = 0.024), whereas the distance obtained in the sit-and-reach-test was likely lower in the RX than in the XX group (15.3 ± 7.8 vs. 18.4 ± 9.9 cm; ES = 0.4 ± 0.4, p = 0.046). Maximal dorsiflexion during the weight-bearing lunge test was different in the RR and XX groups (54.8 ± 5.8 vs. 57.7 ± 5.1 degree; ES = 0.5 ± 0.5, p = 0.044). Maximal isometric force was higher in the RR than in the XX group (16.7 ± 4.7 vs. 14.7 ± 4.0 N/kg; ES = −0.5 ± 0.3, p = 0.038). There was no difference in the energy cost of running between genotypes (~4.8 J/kg/min for all three groups, ES ~0.2 ± 0.4). Conclusions: The ACTN3 genotype might influence several exercise phenotypes in recreational marathoners. Deficiency in α-actinin-3 might be accompanied by higher body fatness, lower muscle strength and higher muscle flexibility and range of motion. Although there is not yet a scientific rationale for the use of commercial genetic tests to predict sports performance, recreational marathon runners who have performed such types of testing and have the ACTN3 XX genotype might perhaps benefit from personalized strength training to improve their performance more than their counterparts with other ACTN3 genotypes.
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More than a ‘speed gene’: ACTN3 R577X genotype, trainability, muscle damage, and the risk for injuries
European Journal of Applied Physiology, 2019Co-Authors: Juan Del Coso, Nir Eynon, Laura M Perez, Danielle Hiam, Peter Houweling, Alejandro LuciaAbstract:A common null polymorphism (rs1815739; R577X) in the gene that codes for α-actinin-3 ( ACTN3 ) has been related to different aspects of exercise performance. Individuals who are homozygous for the X allele are unable to express the α-actinin-3 protein in the muscle as opposed to those with the RX or RR genotype. α-actinin-3 deficiency in the muscle does not result in any disease. However, the different ACTN3 genotypes can modify the functioning of skeletal muscle during exercise through structural, metabolic or signaling changes, as shown in both humans and in the mouse model. Specifically, the ACTN3 RR genotype might favor the ability to generate powerful and forceful muscle contractions. Leading to an overall advantage of the RR genotype for enhanced performance in some speed and power-oriented sports. In addition, RR genotype might also favor the ability to withstand exercise-induced muscle damage, while the beneficial influence of the XX genotype on aerobic exercise performance needs to be validated in human studies. More information is required to unveil the association of ACTN3 genotype with trainability and injury risk during acute or chronic exercise.
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more than a speed gene ACTN3 r577x genotype trainability muscle damage and the risk for injuries
European Journal of Applied Physiology, 2019Co-Authors: Juan Del Coso, Peter J Houweling, Nir Eynon, Laura M Perez, Danielle Hiam, Alejandro LuciaAbstract:A common null polymorphism (rs1815739; R577X) in the gene that codes for α-actinin-3 (ACTN3) has been related to different aspects of exercise performance. Individuals who are homozygous for the X allele are unable to express the α-actinin-3 protein in the muscle as opposed to those with the RX or RR genotype. α-actinin-3 deficiency in the muscle does not result in any disease. However, the different ACTN3 genotypes can modify the functioning of skeletal muscle during exercise through structural, metabolic or signaling changes, as shown in both humans and in the mouse model. Specifically, the ACTN3 RR genotype might favor the ability to generate powerful and forceful muscle contractions. Leading to an overall advantage of the RR genotype for enhanced performance in some speed and power-oriented sports. In addition, RR genotype might also favor the ability to withstand exercise-induced muscle damage, while the beneficial influence of the XX genotype on aerobic exercise performance needs to be validated in human studies. More information is required to unveil the association of ACTN3 genotype with trainability and injury risk during acute or chronic exercise.
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is evolutionary loss our gain the role of ACTN3 p arg577ter r577x genotype in athletic performance ageing and disease
Human Mutation, 2018Co-Authors: Peter J Houweling, Kathryn N North, Jane T Seto, Alejandro Lucia, Ioannis Papadimitriou, Juan Del Coso, Laura M Perez, Nir EynonAbstract:: A common null polymorphism in the ACTN3 gene (rs1815739:C>T) results in replacement of an arginine (R) with a premature stop codon (X) at amino acid 577 in the fast muscle protein α-actinin-3. The ACTN3 p.Arg577Ter allele (aka p.R577* or R577X) has undergone positive selection, with an increase in the X allele frequency as modern humans migrated out of Africa into the colder, less species-rich Eurasian climates suggesting that the absence of α-actinin-3 may be beneficial in these conditions. Approximately 1.5 billion people worldwide are completely deficient in α-actinin-3. While the absence of α-actinin-3 influences skeletal muscle function and metabolism this does not result in overt muscle disease. α-Actinin-3 deficiency (ACTN3 XX genotype) is constantly underrepresented in sprint/power performance athletes. However, recent findings from our group and others suggest that the ACTN3 R577X genotype plays a role beyond athletic performance with effects observed in ageing, bone health, and inherited muscle disorders such as McArdle disease and Duchenne muscle dystrophy. In this review, we provide an update on the current knowledge regarding the influence of ACTN3 R577X on skeletal muscle function and its potential biological and clinical implications. We also outline future research directions to explore the role of α-actinin-3 in healthy and diseased populations.
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ACTN3 r577x and ace i d gene variants influence performance in elite sprinters a multi cohort study
BMC Genomics, 2016Co-Authors: Ioannis Papadimitriou, Alejandro Lucia, Yannis P Pitsiladis, Vladimir P Pushkarev, Dmitry A Dyatlov, Evgeniy F Orekhov, Guilherme Giannini Artioli, Joao Paulo Limongi Franca Guilherme, Antonio Herbert Lancha, Valentina GinevicienėAbstract:To date, studies investigating the association between ACTN3 R577X and ACE I/D gene variants and elite sprint/power performance have been limited by small cohorts from mixed sport disciplines, without quantitative measures of performance. Aim: To examine the association between these variants and sprint time in elite athletes. We collected a total of 555 best personal 100-, 200-, and 400-m times of 346 elite sprinters in a large cohort of elite Caucasian or African origin sprinters from 10 different countries. Sprinters were genotyped for ACTN3 R577X and ACE ID variants. On average, male Caucasian sprinters with the ACTN3 577RR or the ACE DD genotype had faster best 200-m sprint time than their 577XX (21.19 ± 0.53 s vs. 21.86 ± 0.54 s, p = 0.016) and ACE II (21.33 ± 0.56 vs. 21.93 ± 0.67 sec, p = 0.004) counterparts and only one case of ACE II, and no cases of ACTN3 577XX, had a faster 200-m time than the 2012 London Olympics qualifying (vs. 12 qualified sprinters with 577RR or 577RX genotype). Caucasian sprinters with the ACE DD genotype had faster best 400-m sprint time than their ACE II counterparts (46.94 ± 1.19 s vs. 48.50 ± 1.07 s, p = 0.003). Using genetic models we found that the ACTN3 577R allele and ACE D allele dominant model account for 0.92 % and 1.48 % of sprint time variance, respectively. Despite sprint performance relying on many gene variants and environment, the % sprint time variance explained by ACE and ACTN3 is substantial at the elite level and might be the difference between a world record and only making the final.
Peter J Houweling - One of the best experts on this subject based on the ideXlab platform.
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more than a speed gene ACTN3 r577x genotype trainability muscle damage and the risk for injuries
European Journal of Applied Physiology, 2019Co-Authors: Juan Del Coso, Peter J Houweling, Nir Eynon, Laura M Perez, Danielle Hiam, Alejandro LuciaAbstract:A common null polymorphism (rs1815739; R577X) in the gene that codes for α-actinin-3 (ACTN3) has been related to different aspects of exercise performance. Individuals who are homozygous for the X allele are unable to express the α-actinin-3 protein in the muscle as opposed to those with the RX or RR genotype. α-actinin-3 deficiency in the muscle does not result in any disease. However, the different ACTN3 genotypes can modify the functioning of skeletal muscle during exercise through structural, metabolic or signaling changes, as shown in both humans and in the mouse model. Specifically, the ACTN3 RR genotype might favor the ability to generate powerful and forceful muscle contractions. Leading to an overall advantage of the RR genotype for enhanced performance in some speed and power-oriented sports. In addition, RR genotype might also favor the ability to withstand exercise-induced muscle damage, while the beneficial influence of the XX genotype on aerobic exercise performance needs to be validated in human studies. More information is required to unveil the association of ACTN3 genotype with trainability and injury risk during acute or chronic exercise.
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is evolutionary loss our gain the role of ACTN3 p arg577ter r577x genotype in athletic performance ageing and disease
Human Mutation, 2018Co-Authors: Peter J Houweling, Kathryn N North, Jane T Seto, Alejandro Lucia, Ioannis Papadimitriou, Juan Del Coso, Laura M Perez, Nir EynonAbstract:: A common null polymorphism in the ACTN3 gene (rs1815739:C>T) results in replacement of an arginine (R) with a premature stop codon (X) at amino acid 577 in the fast muscle protein α-actinin-3. The ACTN3 p.Arg577Ter allele (aka p.R577* or R577X) has undergone positive selection, with an increase in the X allele frequency as modern humans migrated out of Africa into the colder, less species-rich Eurasian climates suggesting that the absence of α-actinin-3 may be beneficial in these conditions. Approximately 1.5 billion people worldwide are completely deficient in α-actinin-3. While the absence of α-actinin-3 influences skeletal muscle function and metabolism this does not result in overt muscle disease. α-Actinin-3 deficiency (ACTN3 XX genotype) is constantly underrepresented in sprint/power performance athletes. However, recent findings from our group and others suggest that the ACTN3 R577X genotype plays a role beyond athletic performance with effects observed in ageing, bone health, and inherited muscle disorders such as McArdle disease and Duchenne muscle dystrophy. In this review, we provide an update on the current knowledge regarding the influence of ACTN3 R577X on skeletal muscle function and its potential biological and clinical implications. We also outline future research directions to explore the role of α-actinin-3 in healthy and diseased populations.
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the effect of ACTN3 gene doping on skeletal muscle performance
American Journal of Human Genetics, 2018Co-Authors: Peter J Houweling, Marshall W Hogarth, Fleur Garton, Damjan Vukcevic, Lyra R Meehan, Kelly N Roeszler, Chrystal F Tiong, Diana Zannino, Nan YangAbstract:Loss of expression of ACTN3, due to homozygosity of the common null polymorphism (p.Arg577X), is underrepresented in elite sprint/power athletes and has been associated with reduced muscle mass and strength in humans and mice. To investigate ACTN3 gene dosage in performance and whether expression could enhance muscle force, we performed meta-analysis and expression studies. Our general meta-analysis using a Bayesian random effects model in elite sprint/power athlete cohorts demonstrated a consistent homozygous-group effect across studies (per allele OR = 1.4, 95% CI 1.3–1.6) but substantial heterogeneity in heterozygotes. In mouse muscle, rAAV-mediated gene transfer overexpressed and rescued α-actinin-3 expression. Contrary to expectation, in vivo “doping” of ACTN3 at low to moderate doses demonstrated an absence of any change in function. At high doses, ACTN3 is toxic and detrimental to force generation, to demonstrate gene doping with supposedly performance-enhancing isoforms of sarcomeric proteins can be detrimental for muscle function. Restoration of α-actinin-3 did not enhance muscle mass but highlighted the primary role of α-actinin-3 in modulating muscle metabolism with altered fatiguability. This is the first study to express a Z-disk protein in healthy skeletal muscle and measure the in vivo effect. The sensitive balance of the sarcomeric proteins and muscle function has relevant implications in areas of gene doping in performance and therapy for neuromuscular disease.
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no association between ACTN3 r577x and ace i d polymorphisms and endurance running times in 698 caucasian athletes
BMC Genomics, 2018Co-Authors: Ioannis Papadimitriou, Peter J Houweling, Fleur Garton, Pawel Cieszczyk, Sarah J Lockey, Sarah Voisin, Adam J Herbert, Agnieszka Maciejewskaskrendo, Marek Sawczuk, Myosotis MassiddaAbstract:Studies investigating associations between ACTN3 R577X and ACE I/D genotypes and endurance athletic status have been limited by small sample sizes from mixed sport disciplines and lack quantitative measures of performance. Aim: To examine the association between ACTN3 R577X and ACE I/D genotypes and best personal running times in a large homogeneous cohort of endurance runners. We collected a total of 1064 personal best 1500, 3000, 5000 m and marathon running times of 698 male and female Caucasian endurance athletes from six countries (Australia, Greece, Italy, Poland, Russia and UK). Athletes were genotyped for ACTN3 R577X and ACE ID variants. There was no association between ACTN3 R577X or ACE I/D genotype and running performance at any distance in men or women. Mean (SD) marathon times (in s) were for men: ACTN3 RR 9149 (593), RX 9221 (582), XX 9129 (582) p = 0.94; ACE DD 9182 (665), ID 9214 (549), II 9155 (492) p = 0.85; for women: ACTN3 RR 10796 (818), RX 10667 (695), XX 10675 (553) p = 0.36; ACE DD 10604 (561), ID 10766 (740), II 10771 (708) p = 0.21. Furthermore, there were no associations between these variants and running time for any distance in a sub-analysis of athletes with personal records within 20% of world records. Thus, consistent with most case-control studies, this multi-cohort quantitative analysis demonstrates it is unlikely that ACTN3 XX genotype provides an advantage in competitive endurance running performance. For ACE II genotype, some prior studies show an association but others do not. Our data indicate it is also unlikely that ACE II genotype provides an advantage in endurance running.
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analysis of the ACTN3 heterozygous genotype suggests that α actinin 3 controls sarcomeric composition and muscle function in a dose dependent fashion
Human Molecular Genetics, 2016Co-Authors: Marshall W Hogarth, Peter J Houweling, Fleur Garton, Taru Tukiainen, Daniel G Macarthur, Jane T Seto, Kate G R Quinlan, Nan YangAbstract:A common null polymorphism (R577X) in ACTN3 causes α-actinin-3 deficiency in ~18% of the global population. There is no associated disease phenotype, but α-actinin-3 deficiency is detrimental to sprint and power performance in both elite athletes and the general population. However, despite considerable investigation to date, the functional consequences of heterozygosity for ACTN3 are unclear. A subset of studies have shown an intermediate phenotype in 577RX individuals, suggesting dosedependency of α-actinin-3, while others have shown no difference between 577RR and RX genotypes. Here, we investigate the effects of α-actinin-3 expression level by comparing the muscle phenotypes of ACTN3 (HET) mice to ACTN3 [wild-type (WT)] and ACTN3 [knockout (KO)] littermates. We show reduction in α-actinin-3 mRNA and protein in HET muscle compared with WT, which is associated with dose-dependent up-regulation of α-actinin-2, z-band alternatively spliced PDZ-motif andmyotilin at the Z-line, and an incremental shift towards oxidative metabolism. While there is no difference in force generation, HET mice have an intermediate endurance capacity compared with WT and KO. The R577X polymorphism is associated with changes in ACTN3 expression consistent with an additive model in the human genotype-tissue expression cohort, but does not influence any other muscle transcripts, including ACTN2. Overall, ACTN3 influences sarcomeric composition in a dose-dependent fashion in mouse skeletal muscle, which translates directly to function. Variance in fibre type between biopsies likely masks this phenomenon in human skeletal muscle, but we suggest that an additive model is the most appropriate for use in testing ACTN3 genotype associations.
Nir Eynon - One of the best experts on this subject based on the ideXlab platform.
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More than a ‘speed gene’: ACTN3 R577X genotype, trainability, muscle damage, and the risk for injuries
European Journal of Applied Physiology, 2019Co-Authors: Juan Del Coso, Nir Eynon, Laura M Perez, Danielle Hiam, Peter Houweling, Alejandro LuciaAbstract:A common null polymorphism (rs1815739; R577X) in the gene that codes for α-actinin-3 ( ACTN3 ) has been related to different aspects of exercise performance. Individuals who are homozygous for the X allele are unable to express the α-actinin-3 protein in the muscle as opposed to those with the RX or RR genotype. α-actinin-3 deficiency in the muscle does not result in any disease. However, the different ACTN3 genotypes can modify the functioning of skeletal muscle during exercise through structural, metabolic or signaling changes, as shown in both humans and in the mouse model. Specifically, the ACTN3 RR genotype might favor the ability to generate powerful and forceful muscle contractions. Leading to an overall advantage of the RR genotype for enhanced performance in some speed and power-oriented sports. In addition, RR genotype might also favor the ability to withstand exercise-induced muscle damage, while the beneficial influence of the XX genotype on aerobic exercise performance needs to be validated in human studies. More information is required to unveil the association of ACTN3 genotype with trainability and injury risk during acute or chronic exercise.
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more than a speed gene ACTN3 r577x genotype trainability muscle damage and the risk for injuries
European Journal of Applied Physiology, 2019Co-Authors: Juan Del Coso, Peter J Houweling, Nir Eynon, Laura M Perez, Danielle Hiam, Alejandro LuciaAbstract:A common null polymorphism (rs1815739; R577X) in the gene that codes for α-actinin-3 (ACTN3) has been related to different aspects of exercise performance. Individuals who are homozygous for the X allele are unable to express the α-actinin-3 protein in the muscle as opposed to those with the RX or RR genotype. α-actinin-3 deficiency in the muscle does not result in any disease. However, the different ACTN3 genotypes can modify the functioning of skeletal muscle during exercise through structural, metabolic or signaling changes, as shown in both humans and in the mouse model. Specifically, the ACTN3 RR genotype might favor the ability to generate powerful and forceful muscle contractions. Leading to an overall advantage of the RR genotype for enhanced performance in some speed and power-oriented sports. In addition, RR genotype might also favor the ability to withstand exercise-induced muscle damage, while the beneficial influence of the XX genotype on aerobic exercise performance needs to be validated in human studies. More information is required to unveil the association of ACTN3 genotype with trainability and injury risk during acute or chronic exercise.
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is evolutionary loss our gain the role of ACTN3 p arg577ter r577x genotype in athletic performance ageing and disease
Human Mutation, 2018Co-Authors: Peter J Houweling, Kathryn N North, Jane T Seto, Alejandro Lucia, Ioannis Papadimitriou, Juan Del Coso, Laura M Perez, Nir EynonAbstract:: A common null polymorphism in the ACTN3 gene (rs1815739:C>T) results in replacement of an arginine (R) with a premature stop codon (X) at amino acid 577 in the fast muscle protein α-actinin-3. The ACTN3 p.Arg577Ter allele (aka p.R577* or R577X) has undergone positive selection, with an increase in the X allele frequency as modern humans migrated out of Africa into the colder, less species-rich Eurasian climates suggesting that the absence of α-actinin-3 may be beneficial in these conditions. Approximately 1.5 billion people worldwide are completely deficient in α-actinin-3. While the absence of α-actinin-3 influences skeletal muscle function and metabolism this does not result in overt muscle disease. α-Actinin-3 deficiency (ACTN3 XX genotype) is constantly underrepresented in sprint/power performance athletes. However, recent findings from our group and others suggest that the ACTN3 R577X genotype plays a role beyond athletic performance with effects observed in ageing, bone health, and inherited muscle disorders such as McArdle disease and Duchenne muscle dystrophy. In this review, we provide an update on the current knowledge regarding the influence of ACTN3 R577X on skeletal muscle function and its potential biological and clinical implications. We also outline future research directions to explore the role of α-actinin-3 in healthy and diseased populations.
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ACTN3 r577x polymorphism is associated with the incidence and severity of injuries in professional football players
Clinical Journal of Sport Medicine, 2017Co-Authors: Myosotis Massidda, Nir Eynon, Sarah Voisin, Claudia Culigioni, Francesco Piras, Paolo Cugia, Carla Maria CaloAbstract:Objective:The ACTN3 R577X gene variant results in the absence of the α-actinin-3 protein in ∼18% of humans worldwide and has been associated with athletic performance and increased susceptibility to eccentric muscle damage. The aim of this study was to investigate the association between ACTN3 R577X
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ACTN3 r577x gene variant is associated with muscle related phenotypes in elite chinese sprint power athletes
Journal of Strength and Conditioning Research, 2017Co-Authors: Ruoyu Yang, Nir Eynon, Sarah Voisin, Xunzhang Shen, Yubin Wang, Yongnan Fu, Wangyu Xu, David BishopAbstract:Yang, R, Shen, X, Wang, Y, Voisin, S, Cai, G, Fu, Y, Xu, W, Eynon, N, Bishop, DJ, and Yan, X. ACTN3 R577X gene variant is associated with muscle-related phenotypes in elite Chinese sprint/power athletes. J Strength Cond Res 31(4): 1107-1115, 2017-The ACTN3 R577X polymorphism (rs1815739) has been shown to influence athletic performance. The aim of this study was to investigate the prevalence of this polymorphism in elite Chinese track and field athletes, and to explore its effects on athletes' level of competition and lower-extremity power. We compared the ACTN3 R577X genotypes and allele frequencies in 59 elite sprint/power athletes, 44 elite endurance athletes, and 50 healthy controls from Chinese Han origin. We then subcategorized the athletes into international level and national level and investigated the effects of ACTN3 genotype on lower-extremity power. Genotype distribution of the sprint/power athletes was significantly different from endurance athletes (p = 0.001) and controls (p < 0.001). The frequency of the RR genotype was significantly higher in international-level than that in the national-level sprint/power athletes (p = 0.004), with no international-level sprint/power athletes with XX genotype. The best standing long jump and standing vertical jump results of sprint/power athletes were better in the RR than those in the RX + XX genotypes (p = 0.004 and p = 0.001, respectively). In conclusion, the ACTN3 R577X polymorphism influences the level of competition and lower-extremity power of elite Chinese sprint/power athletes. Including relevant phenotypes such as muscle performance in future studies is important to further understand the effects of gene variants on elite athletic performance.
Juan Del Coso - One of the best experts on this subject based on the ideXlab platform.
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ACTN3 R577X Genotype in Professional and Amateur Tennis Players.
Journal of Strength and Conditioning Research, 2020Co-Authors: Victor Moreno-pérez, Reid Machar, David Sanz-rivas, Juan Del CosoAbstract:Several investigations have concluded that the RR genotype in the ACTN3 R577X polymorphism is overrepresented in elite athletes of strength- and power-based sports when compared with nonelite populations, suggesting a positive role of this genotype on physical performance. However, no investigation has been geared to determine the distribution of this polymorphism in elite tennis players. The aim of this study was to compare the frequency distribution of the ACTN3 R577X genotype in professional and nonprofessional tennis players to determine whether this polymorphism has an association with tennis performance. A total of 128 tennis players volunteered to participate in this study. From the total, 56 were professional tennis players (16 were top 10 in Women Tennis Association/Association of Tennis Professionals [WTA/ATP] rankings, 22 were top 100 in WTA/ATP rankings, and 18 were ranked > top 100 in the WTA/ATP rankings), and the remaining 72 were categorized as nonprofessional. Chi-squared tests were used to assess differences in the distribution of RR, RX, and XX genotypes between the different performance categories. The distribution of the RR, RX, and XX genotypes was similar in professional (33.9, 48.2, and 17.9%) and nonprofessional tennis players (37.5, 40.3, and 22.2%; p = 0.650). Furthermore, the distribution of the ACTN3 R577X polymorphism was not different in top 10 (25.0, 50.0, and 25.0%), top 100 (31.8, 50.0, and 18.2%), and WTA/ATP-ranked players (44.4, 44.4, and 11.2%; p = 0.847). These results indicate that the distribution of the ACTN3 R577X genotype is similar in tennis players of very different performance levels. This outcome suggests that the ACTN3 genotype was not associated with elite tennis performance.
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ACTN3 r577x genotype and exercise phenotypes in recreational marathon runners
Genes, 2019Co-Authors: Juan Del Coso, Beatriz Lara, Victor Moreno, Jorge Gutierrezhellin, Gabriel Baltazarmartins, Carlos Ruizmoreno, Millan Aguilarnavarro, Alejandro LuciaAbstract:Background: Homozygosity for the X-allele in the ACTN3 R577X (rs1815739) polymorphism results in the complete absence of α-actinin-3 in sarcomeres of fast-type muscle fibers. In elite athletes, the ACTN3 XX genotype has been related to inferior performance in speed and power-oriented sports; however, its influence on exercise phenotypes in recreational athletes has received less attention. We sought to determine the influence of ACTN3 genotypes on common exercise phenotypes in recreational marathon runners. Methods: A total of 136 marathoners (116 men and 20 women) were subjected to laboratory testing that included measurements of body composition, isometric muscle force, muscle flexibility, ankle dorsiflexion, and the energy cost of running. ACTN3 genotyping was performed using TaqMan probes. Results: 37 runners (27.2%) had the RR genotype, 67 (49.3%) were RX and 32 (23.5%) were XX. There was a difference in body fat percentage between RR and XX genotype groups (15.7 ± 5.8 vs. 18.8 ± 5.5%; effect size, ES, = 0.5 ± 0.4, p = 0.024), whereas the distance obtained in the sit-and-reach-test was likely lower in the RX than in the XX group (15.3 ± 7.8 vs. 18.4 ± 9.9 cm; ES = 0.4 ± 0.4, p = 0.046). Maximal dorsiflexion during the weight-bearing lunge test was different in the RR and XX groups (54.8 ± 5.8 vs. 57.7 ± 5.1 degree; ES = 0.5 ± 0.5, p = 0.044). Maximal isometric force was higher in the RR than in the XX group (16.7 ± 4.7 vs. 14.7 ± 4.0 N/kg; ES = −0.5 ± 0.3, p = 0.038). There was no difference in the energy cost of running between genotypes (~4.8 J/kg/min for all three groups, ES ~0.2 ± 0.4). Conclusions: The ACTN3 genotype might influence several exercise phenotypes in recreational marathoners. Deficiency in α-actinin-3 might be accompanied by higher body fatness, lower muscle strength and higher muscle flexibility and range of motion. Although there is not yet a scientific rationale for the use of commercial genetic tests to predict sports performance, recreational marathon runners who have performed such types of testing and have the ACTN3 XX genotype might perhaps benefit from personalized strength training to improve their performance more than their counterparts with other ACTN3 genotypes.
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More than a ‘speed gene’: ACTN3 R577X genotype, trainability, muscle damage, and the risk for injuries
European Journal of Applied Physiology, 2019Co-Authors: Juan Del Coso, Nir Eynon, Laura M Perez, Danielle Hiam, Peter Houweling, Alejandro LuciaAbstract:A common null polymorphism (rs1815739; R577X) in the gene that codes for α-actinin-3 ( ACTN3 ) has been related to different aspects of exercise performance. Individuals who are homozygous for the X allele are unable to express the α-actinin-3 protein in the muscle as opposed to those with the RX or RR genotype. α-actinin-3 deficiency in the muscle does not result in any disease. However, the different ACTN3 genotypes can modify the functioning of skeletal muscle during exercise through structural, metabolic or signaling changes, as shown in both humans and in the mouse model. Specifically, the ACTN3 RR genotype might favor the ability to generate powerful and forceful muscle contractions. Leading to an overall advantage of the RR genotype for enhanced performance in some speed and power-oriented sports. In addition, RR genotype might also favor the ability to withstand exercise-induced muscle damage, while the beneficial influence of the XX genotype on aerobic exercise performance needs to be validated in human studies. More information is required to unveil the association of ACTN3 genotype with trainability and injury risk during acute or chronic exercise.
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more than a speed gene ACTN3 r577x genotype trainability muscle damage and the risk for injuries
European Journal of Applied Physiology, 2019Co-Authors: Juan Del Coso, Peter J Houweling, Nir Eynon, Laura M Perez, Danielle Hiam, Alejandro LuciaAbstract:A common null polymorphism (rs1815739; R577X) in the gene that codes for α-actinin-3 (ACTN3) has been related to different aspects of exercise performance. Individuals who are homozygous for the X allele are unable to express the α-actinin-3 protein in the muscle as opposed to those with the RX or RR genotype. α-actinin-3 deficiency in the muscle does not result in any disease. However, the different ACTN3 genotypes can modify the functioning of skeletal muscle during exercise through structural, metabolic or signaling changes, as shown in both humans and in the mouse model. Specifically, the ACTN3 RR genotype might favor the ability to generate powerful and forceful muscle contractions. Leading to an overall advantage of the RR genotype for enhanced performance in some speed and power-oriented sports. In addition, RR genotype might also favor the ability to withstand exercise-induced muscle damage, while the beneficial influence of the XX genotype on aerobic exercise performance needs to be validated in human studies. More information is required to unveil the association of ACTN3 genotype with trainability and injury risk during acute or chronic exercise.
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is evolutionary loss our gain the role of ACTN3 p arg577ter r577x genotype in athletic performance ageing and disease
Human Mutation, 2018Co-Authors: Peter J Houweling, Kathryn N North, Jane T Seto, Alejandro Lucia, Ioannis Papadimitriou, Juan Del Coso, Laura M Perez, Nir EynonAbstract:: A common null polymorphism in the ACTN3 gene (rs1815739:C>T) results in replacement of an arginine (R) with a premature stop codon (X) at amino acid 577 in the fast muscle protein α-actinin-3. The ACTN3 p.Arg577Ter allele (aka p.R577* or R577X) has undergone positive selection, with an increase in the X allele frequency as modern humans migrated out of Africa into the colder, less species-rich Eurasian climates suggesting that the absence of α-actinin-3 may be beneficial in these conditions. Approximately 1.5 billion people worldwide are completely deficient in α-actinin-3. While the absence of α-actinin-3 influences skeletal muscle function and metabolism this does not result in overt muscle disease. α-Actinin-3 deficiency (ACTN3 XX genotype) is constantly underrepresented in sprint/power performance athletes. However, recent findings from our group and others suggest that the ACTN3 R577X genotype plays a role beyond athletic performance with effects observed in ageing, bone health, and inherited muscle disorders such as McArdle disease and Duchenne muscle dystrophy. In this review, we provide an update on the current knowledge regarding the influence of ACTN3 R577X on skeletal muscle function and its potential biological and clinical implications. We also outline future research directions to explore the role of α-actinin-3 in healthy and diseased populations.
Kathryn N North - One of the best experts on this subject based on the ideXlab platform.
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is evolutionary loss our gain the role of ACTN3 p arg577ter r577x genotype in athletic performance ageing and disease
Human Mutation, 2018Co-Authors: Peter J Houweling, Kathryn N North, Jane T Seto, Alejandro Lucia, Ioannis Papadimitriou, Juan Del Coso, Laura M Perez, Nir EynonAbstract:: A common null polymorphism in the ACTN3 gene (rs1815739:C>T) results in replacement of an arginine (R) with a premature stop codon (X) at amino acid 577 in the fast muscle protein α-actinin-3. The ACTN3 p.Arg577Ter allele (aka p.R577* or R577X) has undergone positive selection, with an increase in the X allele frequency as modern humans migrated out of Africa into the colder, less species-rich Eurasian climates suggesting that the absence of α-actinin-3 may be beneficial in these conditions. Approximately 1.5 billion people worldwide are completely deficient in α-actinin-3. While the absence of α-actinin-3 influences skeletal muscle function and metabolism this does not result in overt muscle disease. α-Actinin-3 deficiency (ACTN3 XX genotype) is constantly underrepresented in sprint/power performance athletes. However, recent findings from our group and others suggest that the ACTN3 R577X genotype plays a role beyond athletic performance with effects observed in ageing, bone health, and inherited muscle disorders such as McArdle disease and Duchenne muscle dystrophy. In this review, we provide an update on the current knowledge regarding the influence of ACTN3 R577X on skeletal muscle function and its potential biological and clinical implications. We also outline future research directions to explore the role of α-actinin-3 in healthy and diseased populations.
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the effect of heterozygosity for the ACTN3 null allele on human muscle performance
Medicine and Science in Sports and Exercise, 2016Co-Authors: Fleur Garton, Kathryn N NorthAbstract:AB [alpha]-Actinin-3 is primarily expressed in fast (Type II) fibers in the human skeletal muscle. Over 70% of the global population has at least one copy of a loss of function allele because of a premature stop codon in the ACTN3 gene (R577X). Homozygosity for this variant (577XX) occurs in approximately 16% of humans worldwide and results in complete [alpha]-actinin-3 deficiency, which is detrimental to sprint/power performance and alters adaptation to changing physical demands. The functional implications of [alpha]-actinin-3 deficiency have been the subject of over 90 studies; however, the effect of heterozygosity for the ACTN3 null allele is not well documented or understood. Purpose: We reviewed the literature to focus on the most common ACTN3 genotype (577RX) and its effect on human muscle performance. Specifically, we aimed to determine whether the ACTN3 X allele exerts its effect on human performance only when two copies are present (i.e., in an autosomal recessive fashion). Results: Across a spectrum of conditions, three genotype models (additive, dominant, and recessive) were reported. Most studies assessing healthy adults demonstrated that 577RX heterozygotes performed intermediately (additive model) and/or similarly to the RR genotypes (recessive model). Other studies, (aging, disease/injury, elite sprint performance) showed no definitive genetic model. Conclusions: Assessment of the biological link between dosage, regulation, and function for each ACTN3 genotype is required to improve our understanding of its functional effect and biological penetrance in healthy, aging, and disease populations.
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altered ca2 kinetics associated with α actinin 3 deficiency may explain positive selection for ACTN3 null allele in human evolution
PLOS Genetics, 2015Co-Authors: Stewart I Head, Peter J Houweling, Kate G R Quinlan, Stephen Chan, Robyn M Murphy, Soren Wagner, Oliver Friedrich, Kathryn N NorthAbstract:Over 1.5 billion people lack the skeletal muscle fast-twitch fibre protein α-actinin-3 due to homozygosity for a common null polymorphism (R577X) in the ACTN3 gene. α-Actinin-3 deficiency is detrimental to sprint performance in elite athletes and beneficial to endurance activities. In the human genome, it is very difficult to find single-gene loss-of-function variants that bear signatures of positive selection, yet intriguingly, the ACTN3 null variant has undergone strong positive selection during recent evolution, appearing to provide a survival advantage where food resources are scarce and climate is cold. We have previously demonstrated that α-actinin-3 deficiency in the ACTN3 KO mouse results in a shift in fast-twitch fibres towards oxidative metabolism, which would be more “energy efficient” in famine, and beneficial to endurance performance. Prolonged exposure to cold can also induce changes in skeletal muscle similar to those observed with endurance training, and changes in Ca2+ handling by the sarcoplasmic reticulum (SR) are a key factor underlying these adaptations. On this basis, we explored the effects of α-actinin-3 deficiency on Ca2+ kinetics in single flexor digitorum brevis muscle fibres from ACTN3 KO mice, using the Ca2+-sensitive dye fura-2. Compared to wild-type, fibres of ACTN3 KO mice showed: (i) an increased rate of decay of the twitch transient; (ii) a fourfold increase in the rate of SR Ca2+ leak; (iii) a threefold increase in the rate of SR Ca2+ pumping; and (iv) enhanced maintenance of tetanic Ca2+ during fatigue. The SR Ca2+ pump, SERCA1, and the Ca2+-binding proteins, calsequestrin and sarcalumenin, showed markedly increased expression in muscles of KO mice. Together, these changes in Ca2+ handling in the absence of α-actinin-3 are consistent with cold acclimatisation and thermogenesis, and offer an additional explanation for the positive selection of the ACTN3 577X null allele in populations living in cold environments during recent evolution.
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sequence analysis of the equine ACTN3 gene in australian horse breeds
Gene, 2014Co-Authors: Kristen C Thomas, N A Hamilton, Kathryn N North, Peter J HouwelingAbstract:Abstract The sarcomeric α-actinins, encoded by the genes ACTN2 and ACTN3, are major structural components of the Z-line and have high sequence similarity. α-Actinin-2 is present in all skeletal muscle fibres, while α-actinin-3 has developed specialized expression in only type 2 (fast, glycolytic) fibres. A common single nucleotide polymorphism (SNP) in the human ACTN3 gene (R577X) has been found to influence muscle performance in elite athletes and the normal population. For this reason, equine ACTN3 (eACTN3) is considered to be a possible candidate that may influence horse performance. In this study, the intron/exon boundaries and entire coding region of eACTN3 have been sequenced in five Australian horse breeds (Thoroughbred, Arabian, Standardbred, Clydsdale and Shire) and compared to the eACTN3 GenBank sequence. A total of 34 SNPs were identified, of which 26 were intronic and eight exonic. All exonic SNPs were synonymous; however, five intronic SNPs showed significant differences between breeds. A total of 72 horses were genotyped for a SNP located in the promoter region of the eACTN3 gene (g. 1104 G > A) which differed significantly between breed groups. We hypothesize that this polymorphism influences eACTN3 expression and with further studies may provide a novel marker of horse performance in the future.
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ACTN3 allele frequency in humans covaries with global latitudinal gradient
PLOS ONE, 2013Co-Authors: Scott M Friedlander, Kathryn N North, Amanda L Herrmann, Daniel P Lowry, Emily R Mepham, Chris L OrganAbstract:A premature stop codon in ACTN3 resulting in α-actinin-3 deficiency (the ACTN3 577XX genotype) is common in humans and reduces strength, muscle mass, and fast-twitch fiber diameter, but increases the metabolic efficiency of skeletal muscle. Linkage disequilibrium data suggest that the ACTN3 R577X allele has undergone positive selection during human evolution. The allele has been hypothesized to be adaptive in environments with scarce resources where efficient muscle metabolism would be selected. Here we test this hypothesis by using recently developed comparative methods that account for evolutionary relatedness and gene flow among populations. We find evidence that the ACTN3 577XX genotype evolved in association with the global latitudinal gradient. Our results suggest that environmental variables related to latitudinal variation, such as species richness and mean annual temperature, may have influenced the adaptive evolution of ACTN3 577XX during recent human history.
