Human Molecular Genetics Advance Access originally published online on January 4, 2008
Human Molecular Genetics 2008 17(8):1076-1086; doi:10.1093/hmg/ddm380
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An Actn3 knockout mouse provides mechanistic insights into the association between 
-actinin-3 deficiency and human athletic performance
1 Institute for Neuromuscular Research 2 Oncology Research Unit, The Children's Hospital at Westmead, Sydney 2145, NSW, Australia 3 Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney 2006, NSW, Australia 4 School of Medical Sciences, University of New South Wales, Sydney 2052, NSW, Australia 5 Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia 6 Muscle Development Unit, Children's Medical Research Institute, Sydney 2145, NSW, Australia
* To whom correspondence should be addressed at: Institute for Neuromuscular Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, Sydney 2145, NSW, Australia. Tel: +61 298451906; Fax: +61 298453389; Email: kathryn{at}chw.edu.au
Received October 19, 2007; Accepted December 20, 2007
A common nonsense polymorphism (R577X) in the ACTN3 gene results in complete deficiency of the fast skeletal muscle fiber protein 
-actinin-3 in an estimated one billion humans worldwide. The XX null genotype is under-represented in elite sprint athletes, associated with reduced muscle strength and sprint performance in non-athletes, and is over-represented in endurance athletes, suggesting that -actinin-3 deficiency increases muscle endurance at the cost of power generation. Here we report that muscle from Actn3 knockout mice displays reduced force generation, consistent with results from human association studies. Detailed analysis of knockout mouse muscle reveals reduced fast fiber diameter, increased activity of multiple enzymes in the aerobic metabolic pathway, altered contractile properties, and enhanced recovery from fatigue, suggesting a shift in the properties of fast fibers towards those characteristic of slow fibers. These findings provide the first mechanistic explanation for the reported associations between R577X and human athletic performance and muscle function.
The authors wish it to be known that the first two authors should be regarded as joint First Authors.
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