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

Nature Genetics volume 39, pages 1261–1265 (2007)Cite this article

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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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.

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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.

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Authors and Affiliations

  1. Institute for Neuromuscular Research, Children's Hospital at Westmead, Sydney, 2145, New South Wales, 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, 2006, New South Wales, 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, 0200, Australian Capital Territory, Australia

    Gavin A Huttley & Simon Easteal

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

    Jeff W Hook, Frances A Lemckert & Peter W Gunning

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

    Anthony J Kee & Edna C Hardeman

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

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Correspondence to Kathryn N North.

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Competing interests

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

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

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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). https://doi.org/10.1038/ng2122

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