Deficiency of α-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling

Abstract

Sarcomeric α-actinins (α-actinin-2 and -3) are a major component of the Z-disk in skeletal muscle, where they crosslink actin and other structural proteins to maintain an ordered myofibrillar array. Homozygosity for the common null polymorphism (R577X) in ACTN3 results in the absence of fast fiber-specific α-actinin-3 in ∼20% of the general population. α-Actinin-3 deficiency is associated with decreased force generation and is detrimental to sprint and power performance in elite athletes, suggesting that α-actinin-3 is necessary for optimal forceful repetitive muscle contractions. Since Z-disks are the structures most vulnerable to eccentric damage, we sought to examine the effects of α-actinin-3 deficiency on sarcomeric integrity. Actn3 knockout mouse muscle showed significantly increased force deficits following eccentric contraction at 30% stretch, suggesting that α-actinin-3 deficiency results in an increased susceptibility to muscle damage at the extremes of muscle performance. Microarray analyses demonstrated an increase in muscle remodeling genes, which we confirmed at the protein level. The loss of α-actinin-3 and up-regulation of α-actinin-2 resulted in no significant changes to the total pool of sarcomeric α-actinins, suggesting that alterations in fast fiber Z-disk properties may be related to differences in functional protein interactions between α-actinin-2 and α-actinin-3. In support of this, we demonstrated that the Z-disk proteins, ZASP, titin and vinculin preferentially bind to α-actinin-2. Thus, the loss of α-actinin-3 changes the overall protein composition of fast fiber Z-disks and alters their elastic properties, providing a mechanistic explanation for the loss of force generation and increased susceptibility to eccentric damage in α-actinin-3-deficient individuals.

The ACTN3 genotype in soccer players in response to acute eccentric training

“…To detect muscle damage, Martínez-Amat et al (2005 and Vincent et al (2010) suggest the use of speciWc markers of skeletal muscle which has a quick release and high sensitivity, such as the -actin. The results showed that indicators of muscle damage (CK activity and -actin concentrations) are generally higher in ACTN3XX individuals post-eccentric training in accordance with previous studies (Vincent et al 2010;Seto et al 2011). This Wnding is in contrast with Clarkson et al (2005) and Chan et al (2008).…”

Insights into the molecular etiology of exercise-induced inflammation: opportunities for optimizing performance

“…According to Warren et al,65 degradation of contractile proteins may further contribute to strength loss during prolonged (>72 h) muscle injury. Although evidence implicates various other structural and contractile proteins, such as α-actinin-3, in strength loss following damaging exercise,71,72 more research is needed in order to understand the mechanical aspect of their contribution.…”

Effects of aging, exercise, and disease on force transfer in skeletal muscle

“…It is important to note that, although the loss of ACTN3 has been observed in muscular dystrophies (107), within healthy populations this has no impact on muscle force and power due to compensation from ACTN2 and desmin (75,99).…”