ArticleHuman molecular genetics2016
Analysis of the ACTN3 heterozygous genotype suggests that α-actinin-3 controls sarcomeric composition and muscle function in a dose-dependent fashion.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 3 of them syntheses that pooled it.
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Who cites it
31 citing papers in PubMed, 3 syntheses or guidelines pooled it, 48 citations in OpenAlex.
- Association between ACTN3 R577X genotype and risk of non-contact injury in trained athletes: A systematic review.Journal of sport and health science · 2023Pooled it
- Do exercise-associated genes explain phenotypic variance in the three components of fitness? a systematic review & meta-analysis.PloS one · 2021Pooled it
- The Effect of ACTN3 Gene Doping on Skeletal Muscle Performance.American journal of human genetics · 2018Pooled it
- The X genotype of the ACTN3 sports gene is associated with the endurance of the sportsperson from the South Indian population: a short study.European journal of applied physiology · 2026Article
- Interplay between sarcopenia and type 2 diabetes: mechanisms, implications, and therapeutic prospects.Nutrition & diabetes · 2026Review
- Pyroxd1 is essential for murine viability with the homozygous N155S recurrent variant linked to myopathy, muscle hypotrophy and osteopenia.Acta neuropathologica communications · 2026Article
- Outline: The Long-Term Impact of Exercise on Adolescent Growth and Development.Advances in experimental medicine and biology · 2026Review
- Exploring Desmin as a Potential Modifier in Duchenne Muscular Dystrophy-Associated Cardiomyopathy.Acta physiologica (Oxford, England) · 2025Article
- TheSports (Basel, Switzerland) · 2025Article
- Article
- Response To Comment on: "A Systematic Review and Meta-Analysis of the Association Between ACTN3 R577X Genotypes and Performance in Endurance Versus Power Athletes and Non-Athletes".Sports medicine - open · 2025Article
- Impact of Genetic Polymorphisms on Electrochemical Parameters and Acid-Base Disorders in Brazilian Runners During a 105-Kilometer Ultramarathon.Nutrients · 2024Article
- Association between ComplexGenes · 2024Article
- Article
- Effects of Malocclusion on Maximal Aerobic Capacity and Athletic Performance in Young Sub-Elite Athletes.Sports (Basel, Switzerland) · 2023Article
- Prevalence of Polymorphism and Post-Training Expression of ACTN3 (R/X) and ACE (I/D) Genes in CrossFit Athletes.International journal of environmental research and public health · 2023Article
- Genotype Distribution of theGenes · 2022Article
- The association ofBiology of sport · 2022Article
- Association of theGenes · 2022Article
- Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
A common null polymorphism (R577X) in ACTN3 causes α-actinin-3 deficiency in ∼ 18% of the global population. There is no associated disease phenotype, but α-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 α-actinin-3, while others have shown no difference between 577RR and RX genotypes. Here, we investigate the effects of α-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 α-actinin-3 mRNA and protein in HET muscle compared with WT, which is associated with dose-dependent up-regulation of α-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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.