title: An Actn3 knockout mouse provides mechanistic insights into the association between alpha-actinin-3 deficiency and human athletic performance.
abstract: A common nonsense polymorphism (R577X) in the ACTN3 gene results in complete deficiency of the fast skeletal muscle fiber protein alpha-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 alpha-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.
authors.affiliation: Institute for Neuromuscular Research, The Children's Hospital at Westmead, Sydney 2145, NSW, Australia.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.forename: Jane T
authors.initials: JT
authors.lastname: Seto
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.forename: Kate G R
authors.initials: KG
authors.lastname: Quinlan
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Raftery
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.forename: Megan D
authors.initials: MD
authors.lastname: Nicholson
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kee
authors.forename: Edna C
authors.initials: EC
authors.lastname: Hardeman
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gunning
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.forename: Stewart I
authors.initials: SI
authors.lastname: Head
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
mesh_terms: D000185:Actinin / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018656:Muscle Fibers, Fast-Twitch / Q000502:physiology; D018657:Muscle Fibers, Slow-Twitch / Q000502:physiology; D053580:Muscle Strength / Q000235:genetics; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology*; D010807:Physical Endurance / Q000235:genetics*
chemical_list: C525925:Actn3 protein, mouse; D000185:Actinin