Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans


More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein α-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associated with elite athlete status and human muscle performance, suggesting that α-actinin-3 deficiency influences the function of fast muscle fibers. Here we show that loss of α-actinin-3 expression in a knockout mouse model results in a shift in muscle metabolism toward the more efficient aerobic pathway and an increase in intrinsic endurance performance. In addition, we demonstrate that the genomic region surrounding the 577X null allele shows low levels of genetic variation and recombination in individuals of European and East Asian descent, consistent with strong, recent positive selection. We propose that the 577X allele has been positively selected in some human populations owing to its effect on skeletal muscle metabolism.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Generation and analysis of Actn3−/− mice.
Figure 2: Fast muscle fibers in Actn3−/− mice show increased staining for markers of aerobic metabolism.
Figure 3: Actn3−/− muscle shows increased expression of mitochondrial markers, altered metabolic enzyme activity and increased endurance capacity.
Figure 4: The 577X null allele is associated with low genetic diversity and high long-range LD in Europeans and Asians, suggestive of recent positive selection.

Similar content being viewed by others

Accession codes




  1. Mills, M. et al. Differential expression of the actin-binding proteins, α-actinin-2 and -3, in different species: implications for the evolution of functional redundancy. Hum. Mol. Genet. 10, 1335–1346 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. North, K.N. et al. A common nonsense mutation results in α-actinin-3 deficiency in the general population. Nat. Genet. 21, 353–354 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Yang, N. et al. ACTN3 genotype is associated with human elite athletic performance. Am. J. Hum. Genet. 73, 627–631 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Niemi, A.K. & Majamaa, K. Mitochondrial DNA and ACTN3 genotypes in Finnish elite endurance and sprint athletes. Eur. J. Hum. Genet. 13, 965–969 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Clarkson, P.M. et al. ACTN3 genotype is associated with increases in muscle strength in response to resistance training in women. J. Appl. Physiol. 99, 154–163 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Moran, C.N. et al. Association analysis of the ACTN3 R577X polymorphism and complex quantitative body composition and performance phenotypes in adolescent Greeks. Eur. J. Hum. Genet. 15, 88–93 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. The International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).

  8. Wang, E.T., Kodama, G., Baldi, P. & Moyzis, R.K. Global landscape of recent inferred Darwinian selection for Homo sapiens. Proc. Natl. Acad. Sci. USA 103, 135–140 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Voight, B.F., Kudaravalli, S., Wen, X. & Pritchard, J.K. A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Jones, K.J. et al. Deficiency of the syntrophins and α-dystrobrevin in patients with inherited myopathy. Neuromuscul. Disord. 13, 456–467 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Cooper, S.T., Lo, H.P. & North, K.N. Single section Western blot: Improving the molecular diagnosis of the muscular dystrophies. Neurology 61, 93–97 (2003).

    Article  PubMed  Google Scholar 

  12. Reichmann, H., Srihari, T. & Pette, D. Ipsi- and contralateral fiber transformations by cross-reinnervation. A principle of symmetry. Pflugers Arch. 397, 202–208 (1983).

    Article  CAS  PubMed  Google Scholar 

  13. Srere, P.A. Citrate synthase. Methods Enzymol. 13, 3–11 (1969).

    Article  CAS  Google Scholar 

  14. Koch, L.G. & Britton, S.L. Artificial selection for intrinsic aerobic endurance running capacity in rats. Physiol. Genomics 5, 45–52 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Kong, A. et al. A high-resolution recombination map of the human genome. Nat. Genet. 31, 241–247 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Knight, R. et al. PyCogent: a toolkit for making sense from sequence. Genome Biol. 8, R171 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

Download references


We thank T. Henwood (Children's Hospital at Westmead) for NADH and SDH staining. Antibodies to the α-actinins were provided by A. Beggs (Children's Hospital Boston). Antibody 10F5 was provided by J. Hoh (Univ. Sydney). This project was funded in part by a grant (301950) from the Australian National Health and Medical Research Council. D.G.M. and J.T.S. were supported by Australian Postgraduate Awards.

Author information

Authors and Affiliations



D.G.M., N.Y., J.W.H., F.A.L. and P.W.G. generated the knockout mouse; D.G.M., J.T.S., K.G.Q., J.M.R., N.Y., M.R.E., Y.B., A.J.K. and E.C.H. analyzed the knockout mouse phenotype; D.G.M., J.M.R., G.A.H. and S.E. performed the evolutionary analysis; D.G.M. and K.N.N. designed the studies and wrote the paper.

Corresponding author

Correspondence to Kathryn N North.

Ethics declarations

Competing interests

K.N.N. is the named inventor on a patent entitled, “Genotype of Actn3 and Athletic Performance.”

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–4, Supplementary Methods (PDF 653 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

MacArthur, D., Seto, J., Raftery, J. et al. Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. Nat Genet 39, 1261–1265 (2007).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing