Alpha-actinin-3 explained

Alpha-actinin-3, also known as alpha-actinin skeletal muscle isoform 3 or F-actin cross-linking protein, is a protein that in humans is encoded by the ACTN3 gene (named sprinter gene, speed gene or athlete gene) located on chromosome 11. All people have two copies (alleles) of this gene.^{[1] [2]}

Alpha-actinin is an actin-binding protein with multiple roles in different cell types. This gene expression is limited to skeletal muscle. It is localized to the Z-disc and analogous dense bodies, where it helps to anchor the myofibrillar actin filaments.^[3]

Fast versus slow twitch muscle fibers

Skeletal muscle is composed of long cylindrical cells called muscle fibers. There are two types of muscle fibers, slow twitch or muscle contraction (type I) and fast twitch (type II). Slow twitch fibers are more efficient in using oxygen to generate energy, while fast twitch fibers are less efficient. However, fast twitch fibers fire more rapidly, allowing them to generate more power than slow twitch (type I) fibers. Fast twitch fibers and slow twitch fibers are also called white muscle fibers and red muscles fibers, respectively. The alpha-actinin-3 protein is found in type II muscle fibers.

Alleles

An allele (rs1815739; 577X) has been identified in the ACTN3 gene which results in a deficiency of alpha-actinin-3 in the individuals.^{[4] [5]} The X homozygous genotype (ACTN3 577XX) is caused by a C to T transition in exon 16 of the ACTN3 gene, which causes a transformation of an arginine base (R) to a premature stop codon (X) resulting in the rs1815739 mutation causing no production of the alpha-actinin 3 protein in muscle fibers.^[6] The 577XX polymorphism causes no production of alpha-actinin 3 protein which is essential in fast twitch muscle fibers.

It has been speculated that variations in this gene evolved to accommodate the energy expenditure requirements of people in various parts of the world. Over 75% of the persons have one or two copies of ACTN3 577R and have alpha-actinin-3. Homozygous individuals (ACTN3 577XX) have no alpha-actinin-3 (16%-20% of the population),^{[7] [8]} but they have a high level of alpha-actinin-2.

Athletes

There is an association between the ACTN3 R577X polymorphism in sprint and powerlifting performance at an elite level (RR and RX variants are better), and appears to be an association with exercise recovery and lower injury risk. It appears that the XX genotype is associated with higher levels of muscle damage and a longer time required for recovery.

Interactions

ACTN3 has been shown to interact with alpha-actinin-2.^[9]

See also

• Actinin

Further reading

• MacArthur DG, North KN . A gene for speed? The evolution and function of alpha-actinin-3 . BioEssays . 26 . 7 . 786–795 . July 2004 . 15221860 . 10.1002/bies.20061 . 19761762 .
• Beggs AH, Byers TJ, Knoll JH, Boyce FM, Bruns GA, Kunkel LM . Cloning and characterization of two human skeletal muscle alpha-actinin genes located on chromosomes 1 and 11 . The Journal of Biological Chemistry . 267 . 13 . 9281–9288 . May 1992 . 1339456 . 10.1016/S0021-9258(19)50420-3 . free .
• Yürüker B, Niggli V . Alpha-actinin and vinculin in human neutrophils: reorganization during adhesion and relation to the actin network . Journal of Cell Science . 101 (Pt 2) . 2 . 403–414 . February 1992 . 1629252 . 10.1242/jcs.101.2.403 . 101 .
• Pavalko FM, LaRoche SM . Activation of human neutrophils induces an interaction between the integrin beta 2-subunit (CD18) and the actin binding protein alpha-actinin . Journal of Immunology . 151 . 7 . 3795–3807 . October 1993 . 10.4049/jimmunol.151.7.3795 . 8104223 . free .
• Chan Y, Tong HQ, Beggs AH, Kunkel LM . Human skeletal muscle-specific alpha-actinin-2 and -3 isoforms form homodimers and heterodimers in vitro and in vivo . Biochemical and Biophysical Research Communications . 248 . 1 . 134–139 . July 1998 . 9675099 . 10.1006/bbrc.1998.8920 .
• North KN, Yang N, Wattanasirichaigoon D, Mills M, Easteal S, Beggs AH . A common nonsense mutation results in alpha-actinin-3 deficiency in the general population . Nature Genetics . 21 . 4 . 353–354 . April 1999 . 10192379 . 10.1038/7675 . 19882092 .
• Nikolopoulos SN, Spengler BA, Kisselbach K, Evans AE, Biedler JL, Ross RA . The human non-muscle alpha-actinin protein encoded by the ACTN4 gene suppresses tumorigenicity of human neuroblastoma cells . Oncogene . 19 . 3 . 380–386 . January 2000 . 10656685 . 10.1038/sj.onc.1203310 . 22989834 .
• Takada F, Vander Woude DL, Tong HQ, Thompson TG, Watkins SC, Kunkel LM, Beggs AH . Myozenin: an alpha-actinin- and gamma-filamin-binding protein of skeletal muscle Z lines . Proceedings of the National Academy of Sciences of the United States of America . 98 . 4 . 1595–1600 . February 2001 . 11171996 . 29302 . 10.1073/pnas.041609698 . free .
• Bang ML, Mudry RE, McElhinny AS, Trombitás K, Geach AJ, Yamasaki R, Sorimachi H, Granzier H, Gregorio CC, Labeit S . 6 . Myopalladin, a novel 145-kilodalton sarcomeric protein with multiple roles in Z-disc and I-band protein assemblies . The Journal of Cell Biology . 153 . 2 . 413–427 . April 2001 . 11309420 . 2169455 . 10.1083/jcb.153.2.413 .
• Mills M, Yang N, Weinberger R, Vander Woude DL, Beggs AH, Easteal S, North K . Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy . Human Molecular Genetics . 10 . 13 . 1335–1346 . June 2001 . 11440986 . 10.1093/hmg/10.13.1335 .
• Burgueño J, Blake DJ, Benson MA, Tinsley CL, Esapa CT, Canela EI, Penela P, Mallol J, Mayor F, Lluis C, Franco R, Ciruela F . 6 . The adenosine A2A receptor interacts with the actin-binding protein alpha-actinin . The Journal of Biological Chemistry . 278 . 39 . 37545–37552 . September 2003 . 12837758 . 10.1074/jbc.M302809200 . free . 2445/122310 . free .
• Clarkson PM, Devaney JM, Gordish-Dressman H, Thompson PD, Hubal MJ, Urso M, Price TB, Angelopoulos TJ, Gordon PM, Moyna NM, Pescatello LS, Visich PS, Zoeller RF, Seip RL, Hoffman EP . 6 . ACTN3 genotype is associated with increases in muscle strength in response to resistance training in women . Journal of Applied Physiology . 99 . 1 . 154–163 . July 2005 . 15718405 . 10.1152/japplphysiol.01139.2004 . 23205110 .
• Franzot G, Sjöblom B, Gautel M, Djinović Carugo K . The crystal structure of the actin binding domain from alpha-actinin in its closed conformation: structural insight into phospholipid regulation of alpha-actinin . Journal of Molecular Biology . 348 . 1 . 151–165 . April 2005 . 15808860 . 10.1016/j.jmb.2005.01.002 .
• Clarkson PM, Hoffman EP, Zambraski E, Gordish-Dressman H, Kearns A, Hubal M, Harmon B, Devaney JM . 6 . ACTN3 and MLCK genotype associations with exertional muscle damage . Journal of Applied Physiology . 99 . 2 . 564–569 . August 2005 . 15817725 . 10.1152/japplphysiol.00130.2005 .
• Asanuma K, Kim K, Oh J, Giardino L, Chabanis S, Faul C, Reiser J, Mundel P . 6 . Synaptopodin regulates the actin-bundling activity of alpha-actinin in an isoform-specific manner . The Journal of Clinical Investigation . 115 . 5 . 1188–1198 . May 2005 . 15841212 . 1070637 . 10.1172/JCI23371 .
• Niemi AK, Majamaa K . Mitochondrial DNA and ACTN3 genotypes in Finnish elite endurance and sprint athletes . European Journal of Human Genetics . 13 . 8 . 965–969 . August 2005 . 15886711 . 10.1038/sj.ejhg.5201438 . free .
• Triplett JW, Pavalko FM . Disruption of alpha-actinin-integrin interactions at focal adhesions renders osteoblasts susceptible to apoptosis . American Journal of Physiology. Cell Physiology . 291 . 5 . C909–C921 . November 2006 . 16807302 . 10.1152/ajpcell.00113.2006 . 21854341 .

Notes and References

1. Web site: ACTN3 - Alpha-actinin-3 - Homo sapiens (Human) - ACTN3 gene & protein . www.uniprot.org . 22 April 2022 . en.
2. Beggs AH, Byers TJ, Knoll JH, Boyce FM, Bruns GA, Kunkel LM . Cloning and characterization of two human skeletal muscle alpha-actinin genes located on chromosomes 1 and 11 . The Journal of Biological Chemistry . 267 . 13 . 9281–9288 . May 1992 . 1339456 . 10.1016/S0021-9258(19)50420-3 . free .
3. Web site: Entrez Gene: ACTN3 actinin, alpha 3.
4. Book: Epstein . David . The Sports Gene: Inside the Science of Extraordinary Athletic Performance . 2013 . Penguin . 978-1-101-62263-6 .
5. North KN, Yang N, Wattanasirichaigoon D, Mills M, Easteal S, Beggs AH . A common nonsense mutation results in alpha-actinin-3 deficiency in the general population . Nature Genetics . 21 . 4 . 353–354 . April 1999 . 10192379 . 10.1038/7675 . 19882092 .
6. Pickering C, Kiely J . ACTN3: More than Just a Gene for Speed . Frontiers in Physiology . 8 . 1080 . 2017 . 29326606 . 5741991 . 10.3389/fphys.2017.01080 . free .
7. Hogarth MW, Houweling PJ, Thomas KC, Gordish-Dressman H, Bello L, Pegoraro E, Hoffman EP, Head SI, North KN . 6 . Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy . Nature Communications . 8 . 1 . 14143 . January 2017 . 28139640 . 5290331 . 10.1038/ncomms14143 . 2017NatCo...814143H .
8. Deficiency of α-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling . Human Molecular Genetics . 2011. 10.1093/hmg/ddr196. 15 February 2022. Seto. Jane T.. Lek. Monkol. Quinlan. Kate G.R.. Houweling. Peter J.. Zheng. Xi F.. Garton. Fleur. MacArthur. Daniel G.. Raftery. Joanna M.. Garvey. Sean M.. Hauser. Michael A.. Yang. Nan. Head. Stewart I.. North. Kathryn N.. 20. 15. 2914–2927. 21536590. free.
9. Chan Y, Tong HQ, Beggs AH, Kunkel LM . Human skeletal muscle-specific alpha-actinin-2 and -3 isoforms form homodimers and heterodimers in vitro and in vivo . Biochemical and Biophysical Research Communications . 248 . 1 . 134–139 . July 1998 . 9675099 . 10.1006/bbrc.1998.8920 .