ABSTRACT
The α-actinin-3 gene (ACTN3) R577X polymorphism is one of the most highly studied genetic variations associated with human skeletal muscle function and performance. More than 1 billion people worldwide are completely deficient in α-actinin-3 due to homozygosity for the null polymorphism (ACTN3 577XX). Deficiency of α-actinin-3 is associated with reduced muscle force and power, and frequency of the ACTN3 577XX genotype is underrepresented in elite sprint and power athletes compared to population controls. The ACTN3 577X allele has undergone strong, recent positive selection during modern human migration out of Africa, suggesting that inheritance of this allele provides a survival advantage for endurance in colder climes. The combination of human studies and research in the Actn3 knockout (KO) mouse model to date has solidified the association between ACTN3 R577X and human muscle performance and begun to unravel how ACTN3 modifies fast-twitch fiber characteristics and muscle function. In this chapter, we summarize the current research in ACTN3 R577X and discuss the molecular mechanisms that underlie the consequences of α-actinin-3 deficiency, with new insights into implications for the general population beyond athletic performance – in healthy ageing, muscle disuse, and disease.
