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The Effect of Heterozygosity for the ACTN3 Null Allele on Human Muscle Performance

GARTON, FLEUR C.; NORTH, KATHRYN N.

Medicine & Science in Sports & Exercise: March 2016 - Volume 48 - Issue 3 - p 509–520
doi: 10.1249/MSS.0000000000000784
APPLIED SCIENCES
Free

α-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 α-actinin-3 deficiency, which is detrimental to sprint/power performance and alters adaptation to changing physical demands. The functional implications of α-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.

Murdoch Childrens Research Institute, Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, Victoria, AUSTRALIA

Address for correspondence: Kathryn N. North, BSc(Med), MBBS, MD, FRACP, Murdoch Childrens Research Institute, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia; E-mail: Kathryn.north@mcri.edu.au.

Submitted for publication June 2015.

Accepted for publication September 2015.

The ACTN3 gene is one of the most studied of the known genes that influence human performance. ACTN3 encodes for sarcomeric α-actinin-3, which is specifically expressed in fast muscle fibers (all fast glycolytic Type IIx fibers and 50% of fast oxidative Type IIa fibers) (40). A common genetic variant (rs1815739) that results in a premature stop codon (577X) in the ACTN3 gene exists. Homozygosity for the null allele (577XX) results in complete loss of function and absence of the α-actinin-3 protein (45). The nonancestral (X) allele occurs at relatively low frequencies in West (8%) and East African (9%) populations but occurs at much higher frequencies in both European (44%–45%) and Asian populations (53%–54%) (38). Specific environmental variables such as temperature (cold tolerance) and species richness (feast/famine) have been suggested to influence selection of the ACTN3 577 X allele and current worldwide frequencies of the ACTN3 genotype (23).

Evidence from both in vitro and in vivo studies has demonstrated that α-actinin-2, a highly related member of the ACTN gene family, likely contributes to changes in muscle function with α-actinin-3 deficiency. Modifying the balance of α-actinin-2 and α-actinin-3 at the Z-disk of fast fibers influences structural signaling and metabolic protein interactions at the Z-line, which is hypothesized as the likely explanation for human ACTN3 R577X genotype–performance associations (54).

Our initial finding that α-actinin-3 deficiency (ACTN3 577XX) is detrimental to sprint performance has been replicated in 14 other elite sprint/power athlete cohorts from Europe and Asia (22). Similar findings have been demonstrated in nonathlete studies; α-actinin-3 deficiency is associated with significantly slower 40-m sprint times (42), lower isometric maximal voluntary muscle contractions (13,57,59), reduced muscle mass (17,63), and fast fiber area (57). Although a large number of human association studies have quantified the effects of ACTN3 genotype on muscle strength and response to training, there are very few studies that examine the effect of heterozygosity for the ACTN3 577X allele and whether the X allele exerts its phenotypic effects in a recessive, additive, or dominant fashion. Here, we review the literature to focus on the most common ACTN3 genotype (577RX) and its effect on human muscle performance. Our main aim was to determine whether ACTN3 heterozygotes (577RX) perform the same as ACTN3 577RR (autosomal recessive model) across a range of different performance measures. The assessment of heterozygotes was deemed critical for being able to identify whether a consistent genotype–phenotype model existed among current association studies. This, in turn, will influence how athlete and nonathlete data are grouped for analysis in ACTN3 association studies and will provide insight into any functional advantage or disadvantage associated with the ACTN3 577RX genotype.

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ARTICLES ASSESSED TO REVIEW HETEROZYGOUS EFFECT OF ACTN3 R577X

We collected articles for review using the search term “ACTN3” across four search databases (MEDLINE, Scopus, Embase, and ScienceDirect) up until March 20, 2015. These were collated in a citation manager (ENDNOTE) (n = 679), and duplicates were discarded (n = 275). Remaining abstracts (n = 404) were assessed for inclusion if they were published as a peer-reviewed, human association study (n = 91), or meta-analysis (n = 3) examining the R577X polymorphism and physical performance. The heterozygous ACTN3 genotype effect on elite swimming had previously been reviewed, and these articles were excluded (n = 4). Four articles were not reviewed because of duplicated results. Studies that examined genotype frequency of team sport athletes (n = 8) or nonelite specialist athletes (e.g., juniors, international age-group competitors, mountaineers) (n = 4) were considered beyond the scope of this review and were not included. Using the rationale that α-actinin-3 is expressed in fast muscle fibers that can alter with training, age, and disease, ACTN3 577 heterozygous studies were grouped according to their cohort age and level of training. These articles were reviewed under the following headings: sprint/endurance athletes (n = 27), children/adolescents (n = 5), adults (n = 18), older adults (n = 13), and damage and disease (n = 11).

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ELITE SPRINT PERFORMANCE AND THE ACTN3 577RX GENOTYPE

Detrimental genetic effects on muscle function are hypothesized to be most readily observable in elite athletes where every variable counts. The initial discovery in an Australian Caucasian population that the frequency of ACTN3 577X allele was reduced in sprint/power athletes compared with that in controls (P < 0.0001) (60) has been independently replicated in athletes from Finland, Greece, Russia, Spain, United States, Italy, Israel, Poland, Japan, Korea, and Taiwan (22,30,39). In African, Jamaican, and African–American cohorts, the frequency of the ACTN3 577XX genotype is low in both athletes and controls (2%–7%), and the ACTN3 genotype does not have a demonstrable effect on athletic performance (60). Although European and Asian cohorts support the hypothesis that the loss of α-actinin-3 is detrimental to sprint and power performance, none address whether performance effects are specific to the XX genotype and/or whether RX individuals are also affected.

We examined two meta-analyses to determine whether there was evidence for greater odds ratio (OR) and therefore a selective advantage to be the RR genotype over RX in elite sprint athletes. Alfred et al. (5) examined ACTN3 association studies from eight European sprint power cohorts. Using the X-dominant model (that is, they grouped XX/RX genotypes and compared them with RR), there was 1.52 greater odds (95% confidence interval (CI), 1.30–1.77) for a sprinter to be ACTN3 577RR genotype versus RX/XX. A second meta-analysis of 18 studies (performed by Ma et al. [37]) also reported significantly greater odds for a sprinter to be RR and/or RX genotype by testing both the X dominant and the X-recessive model (grouping RR/RX and comparing with XX) (37). Interestingly, the X-recessive model (RR/RX vs XX) had a higher OR (OR, 1.55; 95% CI, 1.21–1.98) compared with that of the X-dominant model (OR, 1.21; 95% CI, 1.03–1.42), suggesting greater likelihood for a sprinter to be RR/RX compared with controls rather than just RR, as suggested in the study of Alfred et al. (5). These studies show consistent OR assessments; however, Ma et al. (37) did not report on ethnic-specific groups and both studies did not assess all possible genotype models.

Interestingly, five studies examining ACTN3 genotype frequency in national sprint/power competitors versus international (world championships and Olympics) competitors have reported an inverse relation with ACTN3 577XX genotype—i.e., the higher the level of competition, the lower the proportion of 577XX individuals (19,21,47). There were consistent reductions in XX frequency (Table 1); however, we were unable to determine whether there was an additive advantage of the RR versus the RX genotype. Three international studies show increased frequency of RR athletes versus RX athletes (+6%, +64%, and +54%), whereas two studies have a reduced RR frequency versus RX (−4%, −7%).

TABLE 1

TABLE 1

Quantitative measures could help resolve whether performance differences exist in ACTN3 RX athletes; however, few studies of this nature exist and only one study has examined sprint performance. Elite male Japanese sprinters with the RR (n = 6) and RX (n = 16) genotypes were reported to be significantly faster than XX sprinters (n = 6) in 100 m but not in 400 m (n = 3RR, 12RX, and 2XX) (39). Although a larger study is still needed, 100-m performance time was consistent with a recessive model that showed no additional advantage for RR versus RX. The recessive model has also been reported in a group of professional soccer players (n = 37) exposed to a bout of eccentric exercise. Individuals with the RR/RX genotype had lower levels of muscle damage markers and higher levels of testosterone and the inflammatory marker interleukin-6 compared with those of 577XX athletes (50). A much larger study testing elite-team sprint and endurance athletes reported a genotype association with testosterone levels. Interestingly, this was consistent with an additive model with differences between the RR and RX individuals. The ACTN3 577R allele resulted in increased levels of serum testosterone that reportedly explained 12.5% and 14.8% of the variance in testosterone in females and males, respectively (1).

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ELITE ENDURANCE ATHLETES AND THE ACTN3 577RX GENOTYPE

The ACTN3 genotype frequency in endurance athletes significantly differs from that in sprint athletes. This was reported in a meta-analysis of five studies (sprint vs endurance athletes, 1.99; 95% CI, 1.19–3.32) (5). However, most studies have compared endurance athletes with controls. Seven of 17 endurance athlete studies (cycling, long-distance running, rowing, and triathlon) have demonstrated a significant association with the ACTN3 genotype (60); however, findings varied across studies, with significant increases (21,60) and decreases (2,12) in XX genotype frequency, accompanied with no consistent increase or decrease in 577RX heterozygotes. Because of these discrepancies, no ACTN3 genotype effect was found in either of the published meta-analyses using a recessive or dominant model (5,37). These results are hypothesized to be due to the demands of modern endurance sport, whereby the prevalence of the R allele may be maintained at the elite level of some sports, as it has a positive effect on finishing sprint ability. The evidence to date suggests that the ACTN3 genotype affects sprint performance but not endurance performance.

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THE ACTN3 577RX GENOTYPE EFFECT IN CHILDREN AND ADOLESCENTS

Five studies have examined the effects of ACTN3 genotype on performance in young adolescents (Table 2). The largest study to date (n = 992 adolescents, 11–18 yr) measured body composition, strength (grip, throw), power (vertical jump, 40-m sprint), and V˙O2max (42). Only 40-m sprint time in males was significantly associated with the ACTN3 genotype. Interestingly, the additive model explained the largest portion (96%) of the genetic variance compared with the X-recessive (79%) or X-dominant models (54%). The ACTN3 genotype accounted for 2.3% of phenotypic variance in 40-m sprint time, with the ACTN3 577R allele contributing to faster times in an additive manner.

TABLE 2

TABLE 2

The remaining studies examined younger cohorts age 10–13 yr. Chiu et al. (11) (n = 60) reported greater improvements in 25-m swim times in RX/XX compared with those in RR over 12 wk in Taiwanese males, consistent with an X-dominant effect. The same authors also examined grip strength, sit-ups, long jump, and run time in Taiwanese girls (n = 170) (10). They found that the ACTN3 577R allele contributed to greater fat-free mass in an additive manner and RR females performed a greater number of sit-ups than RX females but was not significantly greater than the XX performance. Neither of these studies controlled for multiple testing, which may lessen the significance of their findings. Ahmetov et al. (4) measured height, weight, grip strength, and standing long jump in active children (n = 457, 11 yr). RR/RX males had greater body mass than 577XX individuals, consistent with a recessive model. The most recent study in Korean children (n = 856) did not control for gender or report relative measures and found no genotype association (34). These studies report some evidence for an adolescent ACTN3 genotype effect on muscle mass, speed, training response in males, strength, and fat-free mass in females. Considering only studies that control for multiple testing, heterozygotes are similar to RR for muscle mass (X-recessive) and intermediate between RR and XX for speed (additive model).

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THE ACTN3 577RX GENOTYPE EFFECT IN ADULTS

The largest number of published studies has been on the effect of ACTN3 genotype and performance in adults (13 studies) including three assessing the response to training (Table 2). One of the largest cohorts (n = 602) measured muscle size and arm strength with 12-wk training (13). Covarying for age and body mass, ACTN3 577XX women had lower baseline arm strength compared with both RX (P < 0.01) and RR women (P < 0.05). This demonstrated an X-recessive model, with 2.2% of the variance attributed to the ACTN3 genotype. After training, ACTN3 577XX women demonstrated greater absolute and relative strength gains compared with RR; RX heterozygotes displayed an intermediate response consistent with the additive model such that 577XX > RX > RR. Approximately 2% of the variance in absolute and relative arm strength gains in women was explained by ACTN3 genotype.

Walsh et al. (59) also found ACTN3 genotype effects in women (n = 394) but not in men (n = 454) age 22–90 yr. Body mass index (BMI), body composition (dual-energy x-ray absorptiometry), peak shortening, and lengthening torques of the knee extensors at slow (30°·s−1) and fast (180°·s−1) velocities were assessed. Covarying for age and height, heterozygote females had intermediate body mass, BMI, fat mass, and fat-free mass compared with those of RR and XX genotypes (additive model). In addition, 577XX females displayed reduced strength performance compared with RX and RR individuals. Interestingly, pairwise analyses found that RX individuals had a greater knee extensor torque than 577XX in both the shortening and lengthening phases. RR individuals showed no differences compared with the RX heterozygotes in peak knee extensor torque apart from the slow (30°·s−1) lengthening phase. Therefore, in this study, the additive model seemed consistent in the body composition measures, with knee extensor power measures being more consistent with an X-recessive model.

In a smaller study of younger males (n = 90, 18–29 yr), baseline strength was measured at different angular velocities in knee extensors (57). Peak torque values in the static, dynamic shortening and lengthening phases were not different between genotype groups. However, consistent with an additive model, ACTN3 577RX men had an intermediate relative dynamic torque muscle power compared with XX and RR; RR males had the greatest relative torque at the highest speed tested (300°·s−1). A smaller study (n = 57) did not replicate these findings (28) or find differences in measures of anaerobic power and fatigue but did report subject differences in body mass (XX > RR/RX). Two similarly sized studies (approximately 60 males/females) also reported no associations with the ACTN3 genotype in physical characteristics, power, and fatigability output (26,44). Garatachea et al. (24) examined baseline power measures in males (n = 217), females (n = 67), and basketball players (n = 102) (18–29 yr). Basketball players had greater vertical jump and sprint performance compared with those of controls, but there was no association with the ACTN3 genotype with and without adjusting for sex, age, weight, and height.

A larger study of similarly age males (n = 266, 21 ± 3 yr) reported greater thigh area, grip strength, jump height, (relative) knee extension torque at 300°·s−1 and fatigue recovery in RR versus 577XX males (t-test) (9). When RX genotypes were included in ANOVA, significant genotype associations remained only for jump height. RX and RR males recorded similarly greater jump height (approximately 5%) values compared with XX males, in line with a recessive model.

Gentil et al. (27) tested baseline strength in Brazilian males and found no association between the ACTN3 genotype and one-repetition maximum (1RM) bench press or knee extensor torque (60°·s−1). However, in a subset of 40 males involved in 11 wk of resistance training, there were ACTN3 genotype differences in knee extensor muscle thickness, as measured by magnetic resonance imaging. These findings were consistent with an X-recessive model, RR/RX individuals had an increase in muscle thickness compared with 577XX. A similarly aged cohort of Caucasian males (n = 51) found that genotype did not alter strength training response but found RR/RX males demonstrated larger muscle volume, greater power, and greater 1RM strength in the untrained state than XX homozygotes (20). Pimenta et al. (51) performed a study that presented good rationale for cohort size and performance measures and reported a number of genotype–phenotype associations. Well-trained soccer players (n = 200) were assessed for power (jump and sprint) and endurance (shuttle run) performance. Consistent with a recessive model, jump height was greater in RR/RX compared with that in XX individuals. Heterozygotes were not different compared with RR and XX for 10-m sprint speed but were slower than RR individuals at 20- and 30-m distances. V˙O2max, as estimated from the shuttle run, was higher in XX versus that in RR. Heterozygotes show an intermediate performance in both run time and endurance to suggest an additive model.

The largest study of the ACTN3 genotype and performance in young males was carried out in trained (active ≥2 h·d−1) Chinese soldiers (n = 452) (56). No genotype differences were found in body composition and run times (100 m, 400 m steeplechase, and 5000 m); however, RX individuals had intermediate grip strength average compared with 577XX and RR (additive model) (P = 0.021). More recently, Orysiak et al. (46) examined young well-trained males (17 ± 2 yr, n = 200). The ACTN3 genotype was significantly associated with all measures of vertical jump performance consistent with an additive model. ACTN3 577XX individuals produced significantly lower height and relative force compared with those of RX (intermediate) and RR (highest) (P < 0.05) in explosive force tests.

Kikuchi et al. (32) tested anaerobic power performance on a bicycle ergometer and reported an association with the ACTN3 genotype in male (n = 144) but not female (n = 109) well-trained Japanese students (20 ± 2 yr). ACTN3 577 RR and RX individuals showed significantly higher relative peak power than XX (P = 0.045, consistent with X-recessive model). The ACTN3 R577X genotype accounted for 4.6% of the variability in the relative peak power in males (P = 0.006).

In summary, ACTN3 genotype associations have been reported in anthropometric measures (females), baseline muscle strength (males and females), and response to training (males and females). These findings report heterozygotes as intermediates (additive) or grouped with RR (X-recessive) (Table 2). These findings are from large studies (n > 100 same sex) with similarly age, trained participants, supporting stringent cohort criteria for quantitating the genotype effects of ACTN3.

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THE ACTN3 577RX GENOTYPE EFFECT IN OLDER COHORTS

The ACTN3 genotype has been examined as a genetic modified in the response to aging due to fast fiber-specific changes that occur with aging (atrophy, reduced fast fiber motor units, and contractile speed) (25).

Delmonico et al. (16) assessed body composition (DEXA), knee extensor strength (1RM) power, and thigh muscle volume before and after a 10-wk strength training program (n = 157, 50–85 yr). Adjusting for BMI, age, and fat-free mass, 577XX females had higher absolute knee extensor peak power compared with RR and RX females, demonstrating an additive effect of the X allele on muscle power. This is contrary to directions previously reported with the ACTN3 genotype and may reflect differences in cohort age and size. In response to strength training, RR and RX women had greater increases in relative peak power compared with 577XX women. The ACTN3 genotype explained 14.3% of the variation in the change in relative peak power in women, with postanalyses consistent with an additive effect of the X allele. A similar effect was detected in relative peak power training response in men (P = 0.07).

Pereira et al. (49) trained women (n = 139, 65 yr) for 12 wk with high-speed contractions. Similar to Delmonico et al. (16), there were greater training improvements in walk speed, strength, jump performance, and sit-to-stand in RR and RX compared with those in XX women, consistent with the additive model.

A large study (n = 1227) assessing muscle function across the ages with measures of grip strength, chair stand test, and walk speed reported an ACTN3 genotype effect in older males (≥55 yr) (33). ACTN3 577XX males had reduced chair-to-stand performance consistent with an X-recessive model (RR/RX vs XX) that explained 2.5% of the variance.

Two studies assessed change in performance over time. Delmonico et al. (17) tested knee extensor torque, thigh cross-sectional area, a physical performance battery, and 400-m walk time in older adults age 70–79 yr (n = 1367). After 5 yr, ACTN3 577XX males demonstrated greater increase in the time needed to complete a 400-m walk and XX older women had approximately 35% greater risk to develop self-reported difficulties in walking/climbing stairs. These associations demonstrated an additive model, with an intermediate effect in RX individuals.

The second longitudinal study assessed risk of falling in two large female cohorts (n = 1245 and 2918) (31). For each group, they performed a cross-sectional analysis of fallers versus nonfallers at baseline and follow-up and assessed each genetic model. In both cohorts, the RX and XX genotypes were associated with a 33% increased risk of falling, with the genotype effect apparent at both baseline and follow-up assessments. The effect sizes were consistent with dominant X allele effect on falls, although they were unable to rule out the additive model.

Zempo et al. (63) assessed muscle mass (magnetic resonance imaging) and activity in middle-age (n = 82, approximately 50 yr) and older Japanese women (n = 80, approximately 67 yr) There were no genotype differences in physical activity; however, the cross-sectional muscle area in older women was lower in XX women compared with those in RR and RX (consistent with an X-recessive model). Lower bone mineral density (BMD) has been reported in one of two Australian cohorts of older women (61). Using an ANCOVA with age and body mass, whole-body BMD (but not femoral neck BMD) was altered with the ACTN3 genotype. BMD was consistent with an additive genetic model with RR > RX > XX. A regression model estimated that the ACTN3 R577X genotype contributes 1.1% to the variance in BMD.

Four studies in old (>60 yr) and very old (90 yr) cohorts (n = 23–100) have found no associations between the ACTN3 genotype and a range of functional measures (25) . Although these were small studies, the largest study (n > 15,000) also reported no associations with physical characteristics and the ACTN3 genotype (5). Combining large cohorts, this study pooled z-scores to assess performance across the age range of 10–90 yr. Height, weight, and BMI were not associated with the ACTN3 genotype and therefore were not included in physical assessment models. Using an additive model, chair raise time, balance, and 6-min walk tests were not different with ACTN3 genotype; however, there was a trend for grip strength to be reduced in 577XX males compared with that in the RR/RX. Overall, their findings do not support an association with the ACTN3 R577X genotype and these physical measures across a wide population.

The response to training, falls, change in walk speed, thigh area, and BMD show some evidence of an effect of the ACTN3 genotype in the later decades of life (Table 3). A mixture of gene models has been reported, including an X-recessive model, dominant X allele, and additive allele effect (Table 3). Five studies did not show any genotype effects, including a large meta-analysis, which did not report any significant associations with strength or BMI (5). Just one study included an internal replication (31), and thus, more evidence is needed to assess the persisting effects of the ACTN3 genotype on the health status of the aging population.

TABLE 3

TABLE 3

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ACTN3 577RX GENOTYPE EFFECT AND DAMAGE/INJURY

Two studies have examined ACTN3 577 heterozygotes in the response to damage and injury response. A study of older females (n = 150) found that RR and RX women had higher creatine kinase (CK) at baseline compared with that in 577XX women (X-recessive model). CK was in the normal range for all genotypes, and there was no genotype association with CK after an eccentric contraction protocol (14).

Interestingly, the ACTN3 R577X genotype and ankle sprain injury has been investigated in young Chinese infantry (55). The genotype frequency of nonankle sprainers (n = 280) was compared with reoccurring, noncontact ankle sprainers (n = 142). There was a 10% increase in the frequency of 577XX individuals, a 1% decrease in RX, and a 13% decrease of RR individuals in the injury group compared with those in controls. Increased copies of the R allele seem to decrease the risk of experiencing recurrent noncontact ankle sprain injuries (additive model). This is a novel finding linking the ACTN3 genotype to injury association, which correlates with the previous cohort findings demonstrating additive R allele association with muscle strength (56).

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THE ACTN3 577RX GENOTYPE EFFECT AND DISEASE

The effect of the ACTN3 genotype as a potential disease modifier has been explored in muscle, metabolic, and multisystemic disorders in an attempt to explain common variation among patient symptom severity. These studies vary widely in the pathogenic process but show several interesting findings.

Patients with glycogen phosphorylase deficiency (McArdle disease) have severely impaired aerobic oxidative capacity. The ACTN3 genotype has been shown to not associate with broad clinical severity (graded 0–3) but specific to exercise capacity (36). Females with the ACTN3 XX/RX genotypes had higher V˙O2max and oxygen uptake at the ventilatory threshold compared with those in ACTN3 RR patients (consistent with an X-dominant model) (n = 19). The ACTN3 genotype has also been investigated in the progressive myopathy disease Pompe (glycogen storage disorder) (15). The ACTN3 genotype was not associated with 6-min walk, pain, CK level, or vital capacity. However, the ACTN3 577X allele was associated with an earlier onset of the disease (P = 0.02, additive model). The presence of the X allele may alter glycogen availability and breakdown in these diseases; however, given the small patient numbers, further studies are needed.

The ACTN3 genotype has been associated in patients with exertional rhabdomyolysis (ER) (18). Patients with ER have severe muscle breakdown in response to strenuous exercise. The frequency of the 577XX genotype was 20% higher in ER individuals compared with that in controls (36% vs 16%, P < 0.001), which showed an OR of 2.97 (95% CI, 1.3–3.4) using the recessive model. Another study demonstrating greater frequency of the 577XX genotype with disease was in a Mexican population of inflammatory myopathies (dermatomyositis, n = 10; and polymyositis. n = 27) and controls (n = 85) (25). Again, using a recessive model, patients with an inflammatory myopathy were approximately 3times more likely to be 577XX than controls (95% CI, 1.6–6.7; P < 0.001). Altered levels of three enzymes and the ACTN3 genotype were reported; however, these results were not consistent with time, so it remains difficult to comment on the association.

Two diseases have not found any association with the ACTN3 genotype. A family (n = 25) with recurring idiopathic scoliosis (lateral spinal column deviation) showed no association with the ACTN3 genotype and disease presence (58). Strength and respiratory measures in young patients with cystic fibrosis (9 ± 2.5 yr, 31 girls and 35 boys) compared with 113 healthy children were not associated with the ACTN3 genotype (62).

More recently, an ACTN3 X-dominant model was reported in a cohort of 436 patients with heart failure age 58 ± 14 yr (7). A 5-yr follow-up survival curve showed higher mortality in ACTN3 RX/XX patients compared with RR patients (n = 239, P = 0.01) (dominant effect). No baseline heart etiology or clinical characteristics were associated with the ACTN3 genotype, and secondary changes in strength and function were not measured. Given the prevalence of chronic heart failure and high mortality rate, further studies are needed to replicate this possible association.

This set of diverse studies demonstrates a number of different genetic models (three recessive, two dominant, two additive) that do not yet have a biological explanation. These preliminary results demonstrate that the ACTN3 577X genotype influences disease prognosis and that the heterozygous effect may differ depending on the pathology of the disease.

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MOLECULAR AND BIOLOGICAL CHANGES ASSOCIATED WITH ACTN3 577RX HETEROZYGOTES

α-Actinin-3 is primarily expressed in fast skeletal muscle fibers, and four studies have assessed the local muscle effect of heterozygosity compared with RR and 577XX individuals.

In speed skaters (n = 94), the proportion of Type I fibers in the vastus lateralis was significantly lower in RR (52%), RX (57%), and 577XX (62%) subjects (P = 0.049), to demonstrate an additive model in which the ACTN3 genotype explained 4.6% of the variation (3). A slightly larger study in active students (n = 143) did not replicate this association with the ACTN3 genotype and fiber-type composition (43). However, in a subset of individuals exposed to three bouts of sprint exercise, there was reduced response in hypertrophy signaling (mammalian target of rapamycin, mTOR and p70S6 kinase) in 577XX compared with that RR/RX individuals (consistent with an X-recessive model). In addition, there was reduced glycogen breakdown in response to sprint exercise in 577XX genotypes compared with that in RX/RR. A similar finding was reported by Quinlan et al. (52). 577XX individuals had increased glycogen content compared with heterozygotes, with a trend for higher glycogen content in 577XX versus that in RR individuals (RR individuals were not different from RX).

The ACTN3 genotype has been associated with muscle function in a case study of spinal cord injury (>17 yr) disuse (25). Skinned single fibers from the disused quadriceps muscle were tested for force, shortening velocity, passive tension, and calcium sensitivity. Absence of α-actinin-3 resulted in less stiff fast fibers and altered fiber proportions. The heterozygote had intermediate effects in these measures, had the largest fiber diameters (over-dominant model, RX > RR and XX) and had similar unloaded velocity to the RR (recessive model). Four gene models are reported in this case study; although this could be a small study effect, this may also indicate that a different genetic model exists depending on the measure being tested.

More recently, Riedl et al. (53) investigated the effect of the ACTN3 genotype in overweight males and females (n = 177; 58–63 yr; BMI > 29 kg·m−2). ACTN3 genotype frequency was altered in those with type 2 diabetes (n = 49) with an increased frequency both 577XX (+12%) and RX (+5%) genotypes compared with those with normal glucose tolerance (P < 0.05). Skeletal muscle analysis in a cohort with normal glucose tolerance (n = 15–20) demonstrated that ACTN3 transcript was absent in XX, with levels in RX consistent with an additive or recessive model. No compensatory increases were found in ACTN2 mRNA; however, several genes were increased in XX controls compared with those in RR or RX, consistent with additive or X-recessive models, including the structural proteins actin, myotilin, nebulin, capping protein, PDLIM3, titin, and calsarcin 1 and 3. Protein abundance of oxidative enzymes NDUFB8 (complex I) and COX2 (complex IV) was increased in XX > RX > RR (additive model).

These studies present some evidence that the ACTN3 genotype alters structural and metabolic properties of the skeletal muscle, particularly in response to disease or training, which may influence whole-body metabolism. It is difficult to determine the effect for heterozygotes for these measures, given that four genetic models have been described here. We highlight a need to assess the protein levels of α-actinin-3 in the skeletal muscle of heterozygotes at baseline and response to disease or training for mechanistic investigations.

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CONCLUSIONS

In this review, we examined the effects of the ACTN3 genotype on a range of factors that influence skeletal muscle performance, with a primary focus on the most common ACTN3 genotype, ACTN3 577RX. We aimed to assess whether there is a consistent genetic model to explain the effects of the X allele across a spectrum of ages and conditions (i.e., dominant, recessive, or additive).

In elite power athletes, review of the existing meta-analyses found shortfalls in the ability to discriminate between RR and RX genotype effects despite the existence of 15 positive sprint/power athlete association studies. The meta-analyses reported significantly altered OR (approximately 1.5) for both an X-recessive (XX < RX/RR) and X-dominant model (XX/RX < RR) in these populations but could neither discriminate between the two nor examine the additive model (5,37). One quantitative performance study suggests that there is no additional advantage for the RR genotype over the RX genotype; however, larger numbers are still required. For future genotype frequency meta-analyses, we suggest using a model-free approach to concurrently assess all genetic models (as demonstrated by Minelli et al. [41]) rather than performing multiple or limited odds ratio analyses.

In adolescent and adult cohorts, the ACTN3 genotype was associated with measures of strength, power, speed, torque, and the response to training in 15 of 23 studies. These studies report an additive allele and/or a recessive (RR/RX vs XX) gene model, with just three studies showing dominant and/or undetermined gene models. This suggests that in most cases, ACTN3 577 heterozygotes are reported to perform either no differently from RR homozygotes or in an intermediate manner (between RR and XX individuals). From the positive association studies, not all followed a consistent genotype model, even for the same measures in independent studies; e.g., of three studies on male jump height, two showed a recessive model whereas one showed an additive model (9,46,51). In addition, not every measure was consistently associated with the ACTN3 genotype. Differences in study cohort, methods of measurement, cohort size, or ethnicity may explain these results; however, we highlight that many studies do not sufficiently control for multiple testing and/or investigate/report why a particular genetic model best explains the association. Future studies should address these points to improve interpretation of their study results and reduce the risk of false positives.

Gene model variation also existed in studies examining disease onset, risk, capacity, or injury, with three additive, two dominant, and three recessive genetic models being reported. Similar issues to those mentioned previously exist in these studies, including those that stem from small sample sizes that need to be replicated and/or provide greater detail on mechanism before being published.

A fundamental question to ask is this: given that in ACTN3 577XX, homozygosity results in complete deficiency of the α-actinin-3 protein, what is the effect of RX heterozygosity on the level of α-actinin-3 expression? Just one study (of >65) asked this, reporting a recessive model for ACTN3 protein levels in RX heterozygotes (53). Genome-wide RNA-seq data suggest that heterozygotes with a premature stop codon allele do not upregulate the expression of their coding allele (35), which may indicate evidence for posttranscriptional control at protein level for ACTN3. Pairing assessments of the ACTN3 genotype with α-actinin-3 levels in adolescents, adults, disuse, and disease populations may help understand heterozygosity (and therefore appropriate genetic model/s) of the ACTN3 RX genotype in populations with dynamic muscle profiles. More recently, a candidate gene study examining modifiers of strength in young boys with Duchenne muscular dystrophy has found evidence for an R577X ACTN3 genotype association (P = 0.008) (48). The initial baseline results are being followed up longitudinally, and these results will be compared with a double knockout (KO) (Actn3 and dystrophin) mouse model to sufficiently understand whether loss of α-actinin-3 does in fact contribute to disease pathogenesis. This type of study design provides not only greater understanding about disease mechanisms (and therefore avenues for treatment) but also sufficient basis to enhance study power for clinical trials in a rare disease.

Use of the Actn3 KO mouse model has provided a vast amount of detail to support human association studies. Absence of α-actinin-3 in the Actn3 knockout (KO) mouse results in a compensatory upregulation of the closely related protein α-actinin-2 (38). α-Actinin-2 is the only sarcomeric isoform present in ACTN3 KO and human 577XX muscle. In mouse muscle, this has a secondary effect on downstream pathways and binding partners. This includes increases in myofibrillar (desmin, myotilin, y-filamin, ZASP, ALP) and metabolic (COX IV, porin, SERCA1) proteins (29,38,52). Single muscle fibers from Actn3 KO mice remain as fast fibers (as defined by presence of Type IIB myosin); they have altered calcium handling with decreased peak twitch Ca2+ release but improved Ca2+ turnover (increased pump and release rates) to explain their fatigue resistance (29). Consistent with human performance studies, Actn3 KO mice display reduced grip strength, resistance to fatigue, and a shift toward slow/oxidative metabolism in fast fibers due to increased calcineurin signaling (54). Current evidence in the Actn3 KO mouse shows that α-actinin-3 deficiency alters muscle adaptation and shift in fiber type with altered physical demands (25,54), which may help explain the association in human aging, disuse, and athletic performance studies (8,17,22). Although the Actn3 KO mouse model provides an excellent model in which to explore the molecular mechanisms underlying the effects of α-actinin-3 deficiency on skeletal muscle performance, humans possess a much lower relative level of fast fibers and α-actinin-3 in the skeletal muscle. Young Actn3 KO mice have enhanced endurance performance (38) that has not been consistently seen in humans (5). Despite the potential effect size limitations, the reductions in muscle strength, fast fiber size, and BMD, as well as the alterations in oxidative metabolism, glycogen levels and calcineurin activity seen in the Actn3 KO mouse have been replicated in healthy human cohorts. Understanding the effect of the ACTN3 R577X genotype as a modulator of disease, injury, and health status, however, still needs to be addressed. Variation genetic model and the presence/strength of the ACTN3 association may relate to fast-fiber composition and abundance of α-actinin-3. For example, a shift of fast fibers (in response to power training) could reduce the baseline RR versus RX ACTN3 genotype effects to result in a recessive versus additive model.

Interhuman variability across a range of performance phenotypes is likely to be attributable to many thousands of genetic variants (6), and the estimation of the type of gene action at loci underlying quantitative traits, including ACTN3 R577X, remains a major challenge in the field of quantitative genetics. Population genome sequencing can provide an additional layer to risk assessment and health advice for an individual. Although this presents a unique potential for improved precision in the provision of health advice, prognosis, and treatment, we need robust gene association studies that can translate findings for this specific application. Although this includes large longitudinal health studies such as the United Kingdom Biobank project (100,000 individuals to be measured for lean mass, BMD, and cycling performance), studies addressing specific measures and/or mechanism of disease and injury will also be required.

The loss-of-function X allele in the ACTN3 gene is one of the most studied and best replicated variants associated with human skeletal muscle performance, and complementary studies in the Actn3 KO mouse model have provided insights into the biological impact of α-actinin-3 deficiency. Understanding the link between dosage, regulation, and function for each ACTN3 genotype will provide important insights into our understanding of normal genetic variation in human skeletal muscle performance and the role of ACTN3 as a disease modifier.

The authors would like to acknowledge Druzhevskaya et al. for providing further information from their publication.

This work was funded by a grant from the National Health and Medical Research Council of Australia (1002033).

No conflicts of interest are declared.

The results of the present study do not constitute endorsement by the American College of Sports Medicine.

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Keywords:

RS1815739; ALPHA-ACTININ-3; HETEROZYGOUS; QUANTITATIVE TRAIT LOCI

© 2016 American College of Sports Medicine