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 ACTN3gene (named sprinter gene, speed gene or athlete gene) located on chromosome 11. All people have two copies (alleles) of this gene.[5][6]
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.[7]
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.[8][9] The X homozygousgenotype (ACTN3 577XX) is caused by a C to T transition in exon 16 of the ACTN3gene, 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.[10] The 577XX polymorphism causes no production of alpha-actinin 3 protein which is essential in fast twitch muscle fibers.[10]
It has been speculated that variations in this gene evolved to accommodate the energy expenditure requirements of people in various parts of the world.[8]: 155–156 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),[11][12] 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.[10] It appears that the XX genotype is associated with higher levels of muscle damage and a longer time required for recovery.[10]
Interactions
ACTN3 has been shown to interact with alpha-actinin-2.[13]
^ abEpstein D (2013). The Sports Gene: Inside the Science of Extraordinary Athletic Performance. Penguin. ISBN978-1-101-62263-6.[page needed]
^North KN, Yang N, Wattanasirichaigoon D, Mills M, Easteal S, Beggs AH (April 1999). "A common nonsense mutation results in alpha-actinin-3 deficiency in the general population". Nature Genetics. 21 (4): 353–354. doi:10.1038/7675. PMID10192379. S2CID19882092.
^Chan Y, Tong HQ, Beggs AH, Kunkel LM (July 1998). "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. doi:10.1006/bbrc.1998.8920. PMID9675099.
Yürüker B, Niggli V (February 1992). "Alpha-actinin and vinculin in human neutrophils: reorganization during adhesion and relation to the actin network". Journal of Cell Science. 101. 101 ( Pt 2) (2): 403–414. doi:10.1242/jcs.101.2.403. PMID1629252.
Chan Y, Tong HQ, Beggs AH, Kunkel LM (July 1998). "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. doi:10.1006/bbrc.1998.8920. PMID9675099.
North KN, Yang N, Wattanasirichaigoon D, Mills M, Easteal S, Beggs AH (April 1999). "A common nonsense mutation results in alpha-actinin-3 deficiency in the general population". Nature Genetics. 21 (4): 353–354. doi:10.1038/7675. PMID10192379. S2CID19882092.
Nikolopoulos SN, Spengler BA, Kisselbach K, Evans AE, Biedler JL, Ross RA (January 2000). "The human non-muscle alpha-actinin protein encoded by the ACTN4 gene suppresses tumorigenicity of human neuroblastoma cells". Oncogene. 19 (3): 380–386. doi:10.1038/sj.onc.1203310. PMID10656685. S2CID22989834.
Mills M, Yang N, Weinberger R, Vander Woude DL, Beggs AH, Easteal S, North K (June 2001). "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. doi:10.1093/hmg/10.13.1335. PMID11440986.
Clarkson PM, Devaney JM, Gordish-Dressman H, Thompson PD, Hubal MJ, Urso M, et al. (July 2005). "ACTN3 genotype is associated with increases in muscle strength in response to resistance training in women". Journal of Applied Physiology. 99 (1): 154–163. doi:10.1152/japplphysiol.01139.2004. PMID15718405. S2CID23205110.
Franzot G, Sjöblom B, Gautel M, Djinović Carugo K (April 2005). "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. doi:10.1016/j.jmb.2005.01.002. PMID15808860.
Clarkson PM, Hoffman EP, Zambraski E, Gordish-Dressman H, Kearns A, Hubal M, et al. (August 2005). "ACTN3 and MLCK genotype associations with exertional muscle damage". Journal of Applied Physiology. 99 (2): 564–569. doi:10.1152/japplphysiol.00130.2005. PMID15817725.
