title: Deficiency of α-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling.
abstract: Sarcomeric α-actinins (α-actinin-2 and -3) are a major component of the Z-disk in skeletal muscle, where they crosslink actin and other structural proteins to maintain an ordered myofibrillar array. Homozygosity for the common null polymorphism (R577X) in ACTN3 results in the absence of fast fiber-specific α-actinin-3 in ∼20% of the general population. α-Actinin-3 deficiency is associated with decreased force generation and is detrimental to sprint and power performance in elite athletes, suggesting that α-actinin-3 is necessary for optimal forceful repetitive muscle contractions. Since Z-disks are the structures most vulnerable to eccentric damage, we sought to examine the effects of α-actinin-3 deficiency on sarcomeric integrity. Actn3 knockout mouse muscle showed significantly increased force deficits following eccentric contraction at 30% stretch, suggesting that α-actinin-3 deficiency results in an increased susceptibility to muscle damage at the extremes of muscle performance. Microarray analyses demonstrated an increase in muscle remodeling genes, which we confirmed at the protein level. The loss of α-actinin-3 and up-regulation of α-actinin-2 resulted in no significant changes to the total pool of sarcomeric α-actinins, suggesting that alterations in fast fiber Z-disk properties may be related to differences in functional protein interactions between α-actinin-2 and α-actinin-3. In support of this, we demonstrated that the Z-disk proteins, ZASP, titin and vinculin preferentially bind to α-actinin-2. Thus, the loss of α-actinin-3 changes the overall protein composition of fast fiber Z-disks and alters their elastic properties, providing a mechanistic explanation for the loss of force generation and increased susceptibility to eccentric damage in α-actinin-3-deficient individuals.
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Locked Bag 4001, Sydney, NSW 2145, Australia.
authors.forename: Jane T
authors.initials: JT
authors.lastname: Seto
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.forename: Kate G R
authors.initials: KG
authors.lastname: Quinlan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houweling
authors.forename: Xi F
authors.initials: XF
authors.lastname: Zheng
authors.forename: Fleur
authors.initials: F
authors.lastname: Garton
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Raftery
authors.forename: Sean M
authors.initials: SM
authors.lastname: Garvey
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hauser
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Stewart I
authors.initials: SI
authors.lastname: Head
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
mesh_terms: D000185:Actinin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D064211:Connectin; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D016596:Vinculin / Q000235:genetics / Q000378:metabolism
chemical_list: D064211:Connectin; D009124:Muscle Proteins; D000185:Actinin; D016596:Vinculin; D011494:Protein Kinases