An α-actinin-3 Knockout Mouse Suffers Increased Sarcomeric Damage from Eccentric Exercise

Nan Yang, Daniel G. MacArthur, Anthony J. Kee, Emma Kettle, Edna C. Hardeman, Frances Lemckert, Jeff Hook, Peter W. Gunning, Kathryn N. North
2006 Medicine & Science in Sports & Exercise  
Research in α-actinin-3 knockout mice suggests a novel role for α-actinin-3 as a mediator of cell signalling. We took advantage of naturally-occurring human "knockouts" (lacking α-actinin-3 protein) to investigate the consequences of α-actinin-3 deficiency on exercise-induced changes in mitochondrial-related genes and proteins, as well as endurance training adaptations. At baseline, we observed a compensatory increase of α-actinin-2 protein in ACTN3 XX (α-actinin-3 deficient; n = 18) vs ACTN3
more » ... n = 18) vs ACTN3 RR (expressing α-actinin-3; n = 19) participants but no differences between genotypes for markers of aerobic fitness or mitochondrial content and function. There was a main effect of genotype, without an interaction, for RCAN1-4 protein content (a marker of calcineurin activity). However, there was no effect of genotype on exercise-induced expression of genes associated with mitochondrial biogenesis, nor post-training physiological changes. In contrast to results in mice, loss of α-actinin-3 is not associated with higher baseline endurance-related phenotypes, or greater adaptations to endurance exercise training in humans. An important component of the skeletal muscle Z-disk in fast-twitch muscle fibres is α-actinin-3 1 , a protein that interacts with multiple metabolic, structural, and signalling molecules 2 . A common polymorphism in the ACTN3 gene (i.e., the ACTN3 577XX genotype) leads to complete absence of α-actinin-3 protein in the fast-twitch fibres of skeletal muscles. This genotype is underrepresented in elite Australian 3 , Finish 4 , Greek 5 , Russian 6 , Israeli 7 , Polish 8 , and Japanese 9 , power-oriented athletes, which suggests α-actinin-3 deficiency has a negative effect on the function of fast-twitch muscle fibres 10 . There are, however, contradicting findings concerning the influence of the ACTN3 577XX genotype on endurance performance. Although some studies have reported an association between the ACTN3 577XX genotype and endurance status in elite athletes 11 , others have not 12,13 . In contrast to human studies, research in Actn3 knockout mice (Actn3 KO) suggests that the adaptive response to endurance training is influenced by the ACTN3 genotype 14 . After four weeks of endurance training, Actn3 KO mice had greater endurance exercise performance and faster recovery from fatigue, compared with wild type (WT) mice, and this was associated with a shift in the characteristics of fast-twitch muscle fibres toward a more oxidative, slow-twitch phenotype 15,16 . Seto et al. 14 also reported an increase in calcineurin activity (1.9-fold) in the muscle of exercised Actn3 KO mice compared with the WT mice (p = 0.093), which was associated with an increase (2.9-fold) in the Regulator of Calcineurin (RCAN1-4) protein content 17 . Consistent with their observations in mice, there was a also greater protein content of RCAN1-4 in resting muscle samples obtained from ACTN3 577XX versus ACTN3 577RR humans 14 . The molecular mechanisms underlying the modified calcineurin activity when α-actinin-3 is absent appear to be via altered binding of calsarcin-2 to sarcomeric α-actinins. When the α-actinin-3 protein is absent (ACTN3 577XX) there is a compensatory increase in α-actinin-2, which binds more tightly to calsarcin-2 (a negative regulator of calcineurin) 18 . Thus, absence of α-actinin-3 protein (with a compensatory increase in α-actinin-2) has been hypothesised to increase the release and activation of calcineurin 14 . Activated calcineurin is able to
doi:10.1249/00005768-200605001-01445 fatcat:ztqen7nfyjd7zhpgytnxhddave