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.