<i>ACTN3</i> Genotype in Professional Endurance Cyclists

Lucía, Alejandro; Gómez‐Gallego, Félix; Santiago, Catalina; Bandrés, Fernando; Earnest, Conrad P.; Rabadán, Manuel; Alonso, J.M.; Hoyos, Jesús; Córdova, Alfredo; Villa, Gerardo; Foster, Carl

doi:10.1055/s-2006-923862

Cited by 100 publications

(96 citation statements)

References 17 publications

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“…However, other studies have not replicated the association between ACTN3 genotype and elite endurance performance. This suggests that the association between ␣-actinin-3 deficiency and endurance is not as strong as its association with reduced performance in sprint and power activities (2,45,53,55,59,67,84).…”

Section: ␣-Actinin-3 Deficiency Results In Improved Endurance Capacitymentioning

confidence: 97%

A Gene for Speed: The Emerging Role of α-Actinin-3 in Muscle Metabolism

2010

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A common polymorphism (R577X) in the ACTN3 gene results in complete deficiency of ␣-actinin-3 protein in ϳ16% of humans worldwide. The presence of ␣-actinin-3 protein is associated with improved sprint/power performance in athletes and the general population. Despite this, there is evidence that the null genotype XX has been acted on by recent positive selection, likely due to its emerging role in the regulation of muscle metabolism. ␣-Actinin-3 deficiency reduces the activity of glycogen phosphorylase and results in a fundamental shift toward more oxidative pathways of energy utilization. Deficiency of the fast-fiber skeletal muscle protein ␣-actinin-3 is common in the general population due to a polymorphic-null allele in the ACTN3 gene. Numerous independent studies have established that the absence of ␣-actinin-3 is detrimental to sprint and power performance in athletes and in the general population (1,25,55,63,66). The sarcomeric ␣-actinins have long been considered to be primarily structural proteins. However, recent data suggest that ␣-actinin-3 plays a significant role in the regulation of muscle metabolism. ␣-Actinin-3 deficiency results in a shift in the characteristics of fast glycolytic muscle fibers toward those of slow muscle fibers with oxidative metabolism (48,49,62). This review examines the emerging role of ␣-actinin-3 in regulation of skeletal muscle metabolism. The ␣-Actinin Family of ProteinsThe ␣-actinins are a family of actin-binding proteins that have been identified in a diverse range of organisms, suggesting an ancient origin (3,8,33,50). The ␣-actinin protein structure is comprised of three domains; an NH 2 -terminal actin-binding domain, a central rod domain containing four internal repeated 122-amino acid motifs, and a COOH-terminal region containing two EF-hand calcium binding motifs. The four repetitive motifs found in ␣-actinin share homology with spectrin, suggesting a common evolutionary origin of the ␣-actinin proteins and the spectrin family of actin binding cytoskeletal proteins, of which dystrophin is a member (13, 75). There is marked evolutionary conservation of the ␣-actinin genes across species, particularly within the NH 2 -terminal actin-binding domain (9). There are four ␣-actinin genes in humans, ACTN1-ACTN4 (9, 85). ACTN1 and ACTN4 contain functional calcium-sensitive EF hands, whereas the skeletal muscle or sarcomeric ␣-actinins, encoded by ACTN2 and ACTN3, have EF hands that are not calcium sensitive (15). In humans, ␣-actinin-2 is expressed in the heart, in all skeletal muscle fibers, and in the brain, whereas ␣-actinin-3 is expressed only in fast glycolytic skeletal muscle fibers, is not present in cardiac muscle, and has low levels of expression in the brain (50). These two proteins diverged from one another following a gene duplication event over 300 million years ago (mya), but have retained considerable sequence similarity (43). Human ␣-actinin-2 and ␣-actinin-3 are 79% identical and 91% similar at the amino acid level (9, 42).The sarcomeres are repeating un...

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Section: ␣-Actinin-3 Deficiency Results In Improved Endurance Capacitymentioning

confidence: 97%

A Gene for Speed: The Emerging Role of α-Actinin-3 in Muscle Metabolism

2010

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“…Statistical analyses were performed by exact tests of population differentiation, using Arlequin, version 3 (3). Analyses were carried out using 1 Â 10 6 Markov chain steps, and 1 Â 10 5 dememorization steps.…”

Section: Methodsmentioning

confidence: 99%

The ACTN3 R577X Polymorphism in East and West African Athletes

Yang

MacArthur

Wolde

et al. 2007

Medicine &Amp; Science in Sports &Amp; Exercise

110

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. Purpose: To determine the frequency of the ACTN3 R577X polymorphism (functional R allele and nonfunctional X allele) in a variety of African populations and to examine its influence on the success of elite East African endurance runners and West African sprinters. Methods: The R577X polymorphism was genotyped in 198 Ethiopian controls and 76 elite Ethiopian endurance athletes, 158 Kenyan controls and 284 elite Kenyan endurance runners, and 60 Nigerian controls and 62 elite Nigerian power athletes. Statistical analyses were performed by exact tests of population differentiation, using Arlequin, version 3. Analyses were carried out using 1 Â 10 6 Markov chain steps, and 1 Â 10 5 dememorization steps. Results: The frequency of the X allele was extremely low among Kenyans and Nigerians (È1% homozygosity) and higher in Ethiopians (È11% homozygosity). The low baseline frequencies of the three populations tested mean that any associations with sprint performance would likely be obscured. In Ethiopians, where baseline levels of 577XX were about 11%, there was no increased frequency in the endurance athletes. Conclusion: Our data suggest that >-actinin-3 deficiency is not a major influence on performance in African athletes. Key Words: GENETICS, ACTININ-3, AFRICA, RUNNERS, ATHLETIC PERFORMANCE T he actin-binding protein >-actinin-3, encoded by the ACTN3 gene, is a highly conserved component of the contractile machinery in fast skeletal muscle fibers in mammals (7). Homozygosity for a common nonsense polymorphism, R577X, results in complete deficiency of >-actinin-3 in about 16% of the global human population (11). We have previously demonstrated a strong association between the R577X polymorphism and elite athlete status in Australian Caucasian populations, with the >-actinin-3-deficient XX genotype being present at a lower frequency in sprint/power athletes, and at slightly higher frequency in elite female endurance athletes, relative to controls (18). The negative association of the XX genotype with sprint performance was subsequently replicated in a cohort of Finnish elite track and field athletes (10). The possible positive association of XX with endurance performance remains intriguing but uncertain, with two recent smaller studies comparing R577X genotype frequencies between 50 elite endurance cyclists, 52 elite endurance runners, and 123 controls from Spain (6), and 42 male rowers and 102 male controls from Italy (13), finding no significant differences in R577X genotype frequencies between control and athlete groups. R577X genotype has also been associated with muscle function parameters in several large nonathlete cohorts. An analysis of 355 females demonstrated an association between the XX genotype and lower baseline muscle strength (1), whereas a study of older individuals found that R577X genotype influences the response of the quadriceps muscle to strength training (2). In a large cohort of Greek adolescents, the XX genotype was associated with significantly slower performance in a 40-m sprint (9). These ...

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“…Initially, the UPR seeks to re-establish ER homeostasis via translation attenuation to decrease ER load of new proteins, transcriptional activation of chaperone genes to increase the folding capability, and activation of the ER-associated degradation machinery to clear misfolded proteins (Harding et al, 2000;Schroder and Kaufman, 2005). If ER stress is unresolved, apoptosis is triggered (Lucia et al, 2006). Three ER transmembrane proteins are instrumental in co-ordinating the UPR signal.…”

Section: Introductionmentioning

confidence: 99%

P58^IPKinhibits coxsackievirus-induced apoptosis via the PI3K/Akt pathway requiring activation of ATF6a and subsequent upregulation of mitofusin 2

Zhang

Qiu

et al. 2013

Cell Microbiol

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Summary Previously we found that prolonged endoplasmic reticulum (ER) stress caused by coxsackievirus B3 (CVB3) infection led to p58IPK downregulation and subsequent cell apoptosis. This finding implies that p58 IPK expression benefits cell survival and counteracts CVB3-induced apoptosis. In testing this hypothesis, we first found that PI3K/Akt survival pathway is more sensitive than ERK1/2 in response to p58 IPK expression. This finding was further verified by silencing p58 IPK with specific siRNAs, which led to the significant suppression of phosphorylation of Akt (p-Akt) but not ERK1/2. Further, using CVB3-infected cell line expressing dominant negative ATF6a (DN-ATF6a), we found that expression of p58 IPK and p-Akt was significantly reduced, which led to the decreased cell viability. However, when the DN-ATF6a cells were transiently transfected with p58 IPK , an opposite result was obtained. Finally, by CVB3 infection of cells stably expressing p58 IPK , we found that CVB3-induced mitochondriamediated apoptosis was suppressed, which was evidenced by the reduced cytochrome c release and upregulation of the mitochondrial membrane protein mitofusin 2. However, silencing p58 IPK with either specific siRNAs or DN-ATF6a sensitized cells to CVB3-induced apoptosis. These results suggest that p58 IPK suppresses CVB3-induced apoptosis through selective activation of PI3K/Akt pathway that requires activation of ATF6a and subsequently upregulates mitofusin 2.

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ACTN3 Genotype in Professional Endurance Cyclists

Cited by 100 publications

References 17 publications

A Gene for Speed: The Emerging Role of α-Actinin-3 in Muscle Metabolism

A Gene for Speed: The Emerging Role of α-Actinin-3 in Muscle Metabolism

The ACTN3 R577X Polymorphism in East and West African Athletes

P58^IPKinhibits coxsackievirus-induced apoptosis via the PI3K/Akt pathway requiring activation of ATF6a and subsequent upregulation of mitofusin 2

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ACTN3 Genotype in Professional Endurance Cyclists

Cited by 100 publications

References 17 publications

A Gene for Speed: The Emerging Role of α-Actinin-3 in Muscle Metabolism

A Gene for Speed: The Emerging Role of α-Actinin-3 in Muscle Metabolism

The ACTN3 R577X Polymorphism in East and West African Athletes

P58IPKinhibits coxsackievirus-induced apoptosis via the PI3K/Akt pathway requiring activation of ATF6a and subsequent upregulation of mitofusin 2

Contact Info

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P58^IPKinhibits coxsackievirus-induced apoptosis via the PI3K/Akt pathway requiring activation of ATF6a and subsequent upregulation of mitofusin 2