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

Publication ,  Journal Article
Seto, JT; Lek, M; Quinlan, KGR; Houweling, PJ; Zheng, XF; Garton, F; MacArthur, DG; Raftery, JM; Garvey, SM; Hauser, MA; Yang, N; Head, SI; North, KN
Published in: Hum Mol Genet
August 1, 2011

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.

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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

August 1, 2011

Volume

20

Issue

15

Start / End Page

2914 / 2927

Location

England

Related Subject Headings

  • Vinculin
  • Two-Hybrid System Techniques
  • Protein Kinases
  • Polymorphism, Genetic
  • Oligonucleotide Array Sequence Analysis
  • Muscle, Skeletal
  • Muscle Proteins
  • Muscle Contraction
  • Mice, Knockout
  • Mice
 

Citation

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Seto, J. T., Lek, M., Quinlan, K. G. R., Houweling, P. J., Zheng, X. F., Garton, F., … North, K. N. (2011). Deficiency of α-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling. Hum Mol Genet, 20(15), 2914–2927. https://doi.org/10.1093/hmg/ddr196
Seto, Jane T., Monkol Lek, Kate G. R. Quinlan, Peter J. Houweling, Xi F. Zheng, Fleur Garton, Daniel G. MacArthur, et al. “Deficiency of α-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling.Hum Mol Genet 20, no. 15 (August 1, 2011): 2914–27. https://doi.org/10.1093/hmg/ddr196.
Seto JT, Lek M, Quinlan KGR, Houweling PJ, Zheng XF, Garton F, et al. Deficiency of α-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling. Hum Mol Genet. 2011 Aug 1;20(15):2914–27.
Seto, Jane T., et al. “Deficiency of α-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling.Hum Mol Genet, vol. 20, no. 15, Aug. 2011, pp. 2914–27. Pubmed, doi:10.1093/hmg/ddr196.
Seto JT, Lek M, Quinlan KGR, Houweling PJ, Zheng XF, Garton F, MacArthur DG, Raftery JM, Garvey SM, Hauser MA, Yang N, Head SI, North KN. Deficiency of α-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling. Hum Mol Genet. 2011 Aug 1;20(15):2914–2927.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

August 1, 2011

Volume

20

Issue

15

Start / End Page

2914 / 2927

Location

England

Related Subject Headings

  • Vinculin
  • Two-Hybrid System Techniques
  • Protein Kinases
  • Polymorphism, Genetic
  • Oligonucleotide Array Sequence Analysis
  • Muscle, Skeletal
  • Muscle Proteins
  • Muscle Contraction
  • Mice, Knockout
  • Mice