Deficiency of α-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling

• DOI: 10.1093/hmg/ddr196
• Publication Date: 2011-05-03T02:12:06Z
• Authors: Jane T. Seto; Monkol Lek; Kate G.R. Quinlan; Peter J. Houweling; Xi F. Zheng; Fleur Garton; Daniel G. MacArthur; Joanna M. Raftery; Sean M. Garvey; Michael A. Hauser; Nan Yang; Stewart I. Head; Kathryn N. North
• Keywords: Actinin; Myofibril; Nebulin; Tropomyosin

Sarcomeric α-actinins (α-actinin-2 and -3) are a major component of the Z-disk in skeletal muscle, where they crosslink actin other structural proteins to maintain an ordered myofibrillar array. Homozygosity for common null polymorphism (R577X) ACTN3 results absence fast fiber-specific α-actinin-3 ∼20% general population. α-Actinin-3 deficiency is associated with decreased force generation detrimental sprint power performance elite athletes, suggesting that necessary optimal forceful repetitive muscle contractions. Since Z-disks structures most vulnerable eccentric damage, we sought examine effects on sarcomeric integrity. Actn3 knockout mouse showed significantly increased deficits following contraction at 30% stretch, susceptibility damage extremes performance. Microarray analyses demonstrated increase remodeling genes, which confirmed protein level. The loss up-regulation α-actinin-2 resulted no significant changes total pool α-actinins, alterations fiber properties may be related differences functional interactions between α-actinin-3. In support this, proteins, ZASP, titin vinculin preferentially bind α-actinin-2. Thus, overall composition alters their elastic properties, providing mechanistic explanation α-actinin-3-deficient individuals.