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

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          Abstract

          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 (P 0), maximal unloading velocity (V 0) 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 II a and II x fibers was larger in RR compared to XX individuals ( P<0.001). P 0 was similar in both groups over all fiber types. A higher V 0 was observed in type II a 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 V 0 and the larger fast fiber CSA in RR compared to XX genotypes likely contribute to enhanced whole muscle performance during high velocity contractions.

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          Most cited references38

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          The Association of Sport Performance with ACE and ACTN3 Genetic Polymorphisms: A Systematic Review and Meta-Analysis

          Background Genetic polymorphism is suggested to be associated with human physical performance. The angiotensin I-converting enzyme insertion/deletion (ACE I/D) polymorphism and the α-actinin-3 gene (ACTN3) R577X polymorphism have been most widely studied for such association analysis. However, the findings are frequently heterogeneous. We aim to summarize the associations of ACE I/D and ACTN3 R577X with sport performance by means of meta-analysis. Methods We systematically reviewed and quantitatively summarized published studies, until October 31, 2012, on relationship between ACE/ACTN3 genetic polymorphisms and sports performance, respectively. Results A total of 366 articles on ACE and 88 articles on ACTN3 were achieved by literature search. A significant association was found for ACE II genotype compared to D allele carriage (DD+ID) with increased possibility of physical performance (OR, 1.23; 95% CI, 1.05–1.45). With respect to sport discipline, the II genotype was found to be associated with performance in endurance athletes (OR, 1.35; 95% CI, 1.17–1.55). On the other hand, no significant association was observed for ACTN3 RR genotype as compared to X allele carriage (XX+RX) (OR, 1.03; 95% CI, 0.92–1.15). However, when restricted the analyses to power events, a significant association was observed (OR, 1.21; 95% CI, 1.03–1.42). Conclusion Our results provide more solid evidence for the associations between ACE II genotype and endurance events and between ACTN3 R allele and power events. The findings suggest that the genetic profiles might influence human physical performance.
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            ACTN3 (R577X) genotype is associated with fiber type distribution.

            alpha-Actinin-3 is a Z-disc structural protein found only in type II muscle fibers. The X allele of the R577X polymorphism in the ACTN3 gene results in a premature stop codon and alpha-actinin-3 deficiency in XX homozygotes. Associations between the R577X polymorphism and the muscle-power performance of elite athletes have been described earlier. About 45% of the fiber type proportions are determined by genetic factors. The ACTN3 variant could be one of the contributing genes in the heritability of fiber type distribution through its interaction with calcineurin. The aim of this study was to quantify the association between the polymorphism and muscle fiber type distribution and fast-velocity knee extension strength. Ninety healthy young men (18-29 y) were genotyped for ACTN3 R577X. Knee extensor strength was measured isometrically (45 degrees ) and at different dynamic velocities (100-300 degrees /s) on a programmable dynamometer. Twenty-two XX and twenty-two RR subjects underwent a biopsy of the right vastus lateralis muscle. Fiber type composition was determined by immunohistochemistry. Homozygotes for the R allele show significantly higher relative dynamic quadriceps torques at 300 degrees /s, compared with XX carriers (P < 0.05). Fiber type characteristics differed significantly between the two genotype groups. The percentage surface and number of type IIx fibers were greater in the RR than the XX genotype group (P < 0.05), and alpha-actinin-3 protein content is systematically higher in type IIx compared with type IIa fibers (staining intensity ratio IIx to IIa = 1.17). This study shows that the mechanism, by which the ACTN3 polymorphism has its effect on muscle power, might rely on a control function of fiber type proportions.
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              Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy.

              The alpha-actinins are a multigene family of four actin-binding proteins related to dystrophin. The two skeletal muscle isoforms of alpha-actinin (ACTN2 and ACTN3) are major structural components of the Z-line involved in anchoring the actin-containing thin filaments. In humans, ACTN2 is expressed in all muscle fibres, while ACTN3 expression is restricted to a subset of type 2 fibres. We have recently demonstrated that alpha-actinin-3 is absent in approximately 18% of individuals in a range of human populations, and that homozygosity for a premature stop codon (577X) accounts for most cases of true alpha-actinin-3 deficiency. Absence of alpha-actinin-3 is not associated with an obvious disease phenotype, raising the possibility that ACTN3 is functionally redundant in humans, and that alpha-actinin-2 is able to compensate for alpha-actinin-3 deficiency. We now present data concerning the expression of ACTN3 in other species. Genotyping of non-human primates indicates that the 577X null mutation has likely arisen in humans. The mouse genome contains four orthologues which all map to evolutionarily conserved syntenic regions for the four human genes. Murine Actn2 and Actn3 are differentially expressed, spatially and temporally, during embryonic development and, in contrast to humans, alpha-actinin-2 expression does not completely overlap alpha-actinin-3 in postnatal skeletal muscle, suggesting independent function. Furthermore, sequence comparison of human, mouse and chicken alpha-actinin genes demonstrates that ACTN3 has been conserved over a long period of evolutionary time, implying a constraint on evolutionary rate imposed by continued function of the gene. These observations provide a real framework in which to test theoretical models of genetic redundancy as they apply to human populations. In addition we highlight the need for caution in making conclusions about gene function from the phenotypic consequences of loss-of-function mutations in animal knockout models.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                1 March 2016
                2016
                : 11
                : 3
                : e0150594
                Affiliations
                [1 ]Exercise Physiology Research Group, Department of Kinesiology, Faculty of Kinesiology and Rehabilitation Sciences, KU Leuven, Heverlee, Belgium
                [2 ]Physical Activity, Sports & Health Research Group, Department of Kinesiology, Faculty of Kinesiology and Rehabilitation Sciences, KU Leuven, Heverlee, Belgium
                [3 ]Institute of Neuroscience, Université catholique de Louvain, Louvain-la-Neuve, Belgium
                [4 ]Sports Medicine Research Laboratory, Luxembourg Institute of Health, Grand-Duchy of Luxembourg, Luxembourg
                Victoria University, AUSTRALIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SB LM DT CJ LD MT MF. Performed the experiments: SB MR RVT. Analyzed the data: SB LM DT LD MT. Contributed reagents/materials/analysis tools: SB MR RVT LM DT CJ LD MT MF. Wrote the paper: SB LM DT LD MT MF.

                ‡ These authors are joint senior authors on this work.

                Article
                PONE-D-15-37252
                10.1371/journal.pone.0150594
                4773019
                26930663
                b8be6150-75cd-482c-b66b-c8bb5eed4b16
                © 2016 Broos et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 28 September 2015
                : 17 February 2016
                Page count
                Figures: 2, Tables: 2, Pages: 11
                Funding
                The present study was funded by a grant of Research Foundation - Flanders (KAN20101.5.100.10) http://www.fwo.be/en/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Muscle Fibers
                Skeletal Muscle Fibers
                Slow-Twitch Muscle Fibers
                Biology and Life Sciences
                Anatomy
                Musculoskeletal System
                Muscles
                Muscle Fibers
                Skeletal Muscle Fibers
                Slow-Twitch Muscle Fibers
                Medicine and Health Sciences
                Anatomy
                Musculoskeletal System
                Muscles
                Muscle Fibers
                Skeletal Muscle Fibers
                Slow-Twitch Muscle Fibers
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Muscle Fibers
                Biology and Life Sciences
                Anatomy
                Musculoskeletal System
                Muscles
                Muscle Fibers
                Medicine and Health Sciences
                Anatomy
                Musculoskeletal System
                Muscles
                Muscle Fibers
                Biology and Life Sciences
                Physiology
                Muscle Physiology
                Muscle Contraction
                Medicine and Health Sciences
                Physiology
                Muscle Physiology
                Muscle Contraction
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Muscle Fibers
                Skeletal Muscle Fibers
                Fast-Twitch Muscle Fibers
                Biology and Life Sciences
                Anatomy
                Musculoskeletal System
                Muscles
                Muscle Fibers
                Skeletal Muscle Fibers
                Fast-Twitch Muscle Fibers
                Medicine and Health Sciences
                Anatomy
                Musculoskeletal System
                Muscles
                Muscle Fibers
                Skeletal Muscle Fibers
                Fast-Twitch Muscle Fibers
                Biology and Life Sciences
                Anatomy
                Musculoskeletal System
                Limbs (Anatomy)
                Legs
                Knees
                Medicine and Health Sciences
                Anatomy
                Musculoskeletal System
                Limbs (Anatomy)
                Legs
                Knees
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Biopsy
                Physical Sciences
                Physics
                Classical Mechanics
                Motion
                Torque
                Research and Analysis Methods
                Bioassays and Physiological Analysis
                Muscle Analysis
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                All relevant data are within the paper and its Supporting Information files.

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