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

Nature Genetics 39, 1261–1265 (2007) | Download Citation

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Abstract

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.

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Acknowledgements

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

Affiliations

  1. Institute for Neuromuscular Research, Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia.

    • Daniel G MacArthur
    • , Jane T Seto
    • , Joanna M Raftery
    • , Kate G Quinlan
    • , Yemima Berman
    • , Nan Yang
    •  & Kathryn N North

  2. Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, New South Wales 2006, Australia.

    • Daniel G MacArthur
    • , Jane T Seto
    • , Kate G Quinlan
    • , Peter W Gunning
    •  & Kathryn N North

  3. John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.

    • Gavin A Huttley
    •  & Simon Easteal

  4. Oncology Research Unit, Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia.

    • Jeff W Hook
    • , Frances A Lemckert
    •  & Peter W Gunning

  5. Muscle Development Unit, Children's Medical Research Institute, Sydney, New South Wales 2145, Australia.

    • Anthony J Kee
    •  & Edna C Hardeman

  6. Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.

    • Michael R Edwards

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Contributions

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.

Competing interests

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

Corresponding author

Correspondence to Kathryn N North.

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DOI

https://doi.org/10.1038/ng2122

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