The human sarcomeric alpha-actinins (ACTN2 and ACTN3) are major structural components of the Z line in skeletal muscle; they play a role in the maintenance of sarcomeric integrity and also interact with a wide variety of structural, signaling and metabolic proteins. ACTN2 is expressed in all muscle fibers, and expression of ACTN3 is restricted to the type 2 (fast glycolytic) fibers that are responsible for forceful contraction at high velocity. There is a common stop codon polymorphism R577X in the ACTN3 gene. Homozygosity for the R577X null-allele results in the absence of alpha-actinin-3 in fast muscle fibers with frequencies that vary from < 1% in Africans to approximately 18% in Caucasians. A number of association studies have demonstrated that the ACTN3 R577X genotype influences athletic performance in Caucasians; the frequency of the XX genotype is significantly lower than controls in sprint athletes, and it appears that alpha-actinin-3 deficiency is detrimental to sprint performance. In the general population, the ACTN3 genotype contributes to the normal variations in muscle strength and sprinting speed. In an Actn3 knockout mouse model, alpha-actinin-3 deficiency is associated with a shift in the characteristics of fast, glycolytic 2B muscle fibers towards a slow phenotype, with decreased muscle mass and fiber diameter, slower contractile properties, increased fatigue resistance, and an increase in oxidative enzyme activity. The shift towards a more efficient oxidative metabolism may underlie the selective advantage of the X-allele during evolution. In turn, the shift towards a 'slow' muscle phenotype in fast muscle fibers likely explains why loss of alpha-actinin-3 is detrimental to sprint performance.
2009 S. Karger AG, Basel