| First Author | Hogarth MW | Year | 2016 |
| Journal | Hum Mol Genet | Volume | 25 |
| Issue | 5 | Pages | 866-77 |
| PubMed ID | 26681802 | Mgi Jnum | J:229312 |
| Mgi Id | MGI:5751617 | Doi | 10.1093/hmg/ddv613 |
| Citation | Hogarth MW, et al. (2016) Analysis of the ACTN3 heterozygous genotype suggests that alpha-actinin-3 controls sarcomeric composition and muscle function in a dose-dependent fashion. Hum Mol Genet 25(5):866-77 |
| abstractText | A common null polymorphism (R577X) in ACTN3 causes alpha-actinin-3 deficiency in approximately 18% of the global population. There is no associated disease phenotype, but alpha-actinin-3 deficiency is detrimental to sprint and power performance in both elite athletes and the general population. However, despite considerable investigation to date, the functional consequences of heterozygosity for ACTN3 are unclear. A subset of studies have shown an intermediate phenotype in 577RX individuals, suggesting dose-dependency of alpha-actinin-3, while others have shown no difference between 577RR and RX genotypes. Here, we investigate the effects of alpha-actinin-3 expression level by comparing the muscle phenotypes of Actn3(+/-) (HET) mice to Actn3(+/+) [wild-type (WT)] and Actn3(-/-) [knockout (KO)] littermates. We show reduction in alpha-actinin-3 mRNA and protein in HET muscle compared with WT, which is associated with dose-dependent up-regulation of alpha-actinin-2, z-band alternatively spliced PDZ-motif and myotilin at the Z-line, and an incremental shift towards oxidative metabolism. While there is no difference in force generation, HET mice have an intermediate endurance capacity compared with WT and KO. The R577X polymorphism is associated with changes in ACTN3 expression consistent with an additive model in the human genotype-tissue expression cohort, but does not influence any other muscle transcripts, including ACTN2. Overall, ACTN3 influences sarcomeric composition in a dose-dependent fashion in mouse skeletal muscle, which translates directly to function. Variance in fibre type between biopsies likely masks this phenomenon in human skeletal muscle, but we suggest that an additive model is the most appropriate for use in testing ACTN3 genotype associations. |
