Abstract
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 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.
Highlights
An important component of the skeletal muscle Z-disk in fast-twitch muscle fibres is α-actinin-31, a protein that interacts with multiple metabolic, structural, and signalling molecules[2]
In addition to genotyping in duplicate, we confirmed that the α-actinin-3 protein was present in ACTN3 RR and not ACTN3 XX participants
While there was a main effect of genotype for RCAN1-4 protein content, there was no significant interaction effect for exercise-induced changes in any of the measured genes or proteins associated with mitochondrial biogenesis
Summary
An important component of the skeletal muscle Z-disk in fast-twitch muscle fibres is α-actinin-31, 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. Seto et al.[14] reported an increase in calcineurin activity (1.9-fold) in the muscle of exercised Actn[3] 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 greater protein content of RCAN1-4 in resting muscle samples obtained from ACTN3 577XX versus ACTN3 577RR humans[14]. While knocking out genes in humans is ethically off-limits, the high percentage of the human population in which the α-actinin-3 protein is absent (i.e., naturally occurring human “knockouts”) affords us the unique opportunity to study the consequences of α-actinin-3 deficiency on human skeletal muscle
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