α-Actinin-3: a novel genetic modifier of duchenne muscular dystrophy

Abstract

Homozygosity for a common null polymorphism (R577X) in the ACTN3 gene results in deficiency of the fast muscle fiber protein, α-actinin-3, in ~18% of the world’s population. ACTN3 genotype significantly influences muscle performance in elite athletes and in the general population. There is also considerable inter-patient variability in Duchenne muscular dystrophy (DMD), some of which is caused by the modifying effects of genes independent of the causative mutation in dystrophin. On this basis, we tested ACTN3 as a genetic modifier of DMD. Here we show that α-actinin-3 deficiency significantly reduces muscle strength in both mdx mice and XX patients, providing strong evidence for ACTN3 as a genetic modifier of DMD. We also show that α-actinin-3 deficiency protects against stretch-induced damage and slows the accumulation of branched fibres in aged mdx muscle, suggesting an amelioration of disease progression. Slow muscle fibres are known to be relatively spared from the pathogenesis of DMD, and we demonstrate a shift towards a slow twitch muscle phenotype in Actn3 KO mdx muscle. In particular the shift towards aerobic metabolism, caused by increased activity of calcineurin and AMP-activated protein kinase, protects α-actinin-3 deficient muscle against the progression of dystrophic pathology in mdx mice. Genetic modifiers have immediate importance in the stratification and analysis of results of therapeutic trials and have the potential to provide insight into the molecular pathogenesis of DMD. Our studies in Actn3-/- mdx mice suggest that α-actinin-3 deficiency is detrimental to muscle performance in DMD at baseline, but ameliorates the progression of dystrophic pathology over time.