Is evolutionary loss our gain? The role of ACTN3 p.Arg577Ter (R577X) genotype in athletic performance, ageing, and disease

Abstract

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.

Influence of the ACTN3 R577X genotype on the injury epidemiology of marathon runners

“…This finding is based on several studies that showed a higher frequency of the ACTN3 RR genotype in elite sprint/power athletes when compared with control groups composed of non-athletes (see reference [9] for a more concise analysis). On the contrary, a higher representation of the ACTN3 XX genotype has been found in some populations of elite endurance athletes [13,14], but this finding has not been replicated in other cohorts of endurance athletes [9]. Thus, current evidence suggests that XX genotype might negatively influence elite sprint/power-based exercise with little or no effect on endurance-based exercise.…”

“…Individuals with the XX genotype, as opposed to those with the RX or RR genotypes, are unable to express α-actinin-3 in fast-type muscle fibers [32]. Although XX individuals compensate for the deficiency of α-actinin-3 with a higher expression of α-actinin-2 [9], this does not prevent a diminished muscle function in humans [33,34]. In addition, α-actinin-3 deficient runners presented higher values of exercise muscle damage in endurance [17], and ultraendurance events [35].…”

“…This SNP leads to the replacement of an arginine (R) base with a premature stop codon (X) that halts the production of functional α-actinin-3 in fast-type muscle fibers. Thus, individuals with the ACTN3 XX genotype have a deficiency of α-actinin-3, an actin-binding protein with a pivotal role in muscle structure and metabolism [9]. In contrast, RX and RR individuals can express α-actinin-3 in fast-type muscle fibers, although recent evidence suggests dose-dependency for α-actinin-3 expression in RX vs. RR individuals [10].…”

“…The deficiency of α-actinin-3 has no clinical impact, but it has been demonstrated that it negatively affects those involved in sprint-based and power-based sports [11], likely due to decreased capacity of muscle fiber to produce force in the absence of α-actinin-3 [12]. This finding is based on several studies that showed a higher frequency of the ACTN3 RR genotype in elite sprint/power athletes when compared with control groups composed of non-athletes (see reference [9] for a more concise analysis). On the contrary, a higher representation of the ACTN3 XX genotype has been found in some populations of elite endurance athletes [13,14], but this finding has not been replicated in other cohorts of endurance athletes [9].…”

Can Genetic Testing Identify Talent for Sport?

“…Recent advances in genetic technology have allowed for greater exploration of the genetic underpinnings of elite performance, leading to the identification of single nucleotide polymorphisms (SNPs) and other genetic variants with the potential to influence sports performance, either directly or indirectly. For example, a SNP in ACTN3, R577X (rs1815739), has been shown to modify the attainment of elite speed-power athlete status [4,5]. Here, a common C-to-T base substitution results in the transformation of an arginine base (R) to a premature stop codon (X).…”