Alpha-Actinins and skeletal muscle performance team

Dr Nan Yang (Team leader), Daniel MacArthur (PhD student), Jane Seto (PhD student), Joanna Raftery (Research assistant), Gregory D'Cruz (Research assistant)

The alpha-actinins are a very important group of proteins that bind to actin. Our team in the Institute of Neuromuscular Research has a particular interest in two members of this group, alpha-actinin-2 and alpha-actinin-3, because they are present in human skeletal muscles. These two proteins reside in a central position in skeletal muscle known as the Z line, where they hold together actin-containing structures, and maintain the muscle contractile apparatus.

In 1999 our group found that alpha-actinin-3 is absent (deficient) in the skeletal muscles of a large proportion of healthy humans. The absence of this protein is due to a "mistake" in the gene encoding alpha-actinin-3 which changes the amino acid Arginine (R) to an early terminator (X). This mistake subsequently creates two forms of the alpha-actinin-3 gene in human: R (normal) and X (deficient).

The absence of alpha-actinin-3 does not cause disease in humans. However, we wondered whether the absence of this protein might affect muscle function at the extremes of human performance - in elite athletes. We collaborated with the Australian Institute of Sport, and investigated alpha-actinin-3 deficiency in a group of Caucasian athletes. By comparison to the general Australian Caucasian population, in whom the frequency of alpha-actinin-3 deficiency is ~18%, we found that the deficiency rate in athletes who performed speed/power competitions is extremely low (~5%). Remarkably, all female athletes, along with all Olympian athletes, were found to have alpha-actinin-3. We therefore became the first group in the world to show it is important to have alpha-actinin-3 to perform in sprint events at an elite level.

In support of these results, alpha-actinin-3 was recently shown by a research group in the USA to influence muscle strength in non-athlete women. All scientific work so far indicates that alpha-actinin-3 has a wide effect in human muscle health and fitness. In the alpha-actinin team, we are setting our long term goals to investigate the possibility of using alpha-actinin-3 to improve human skeletal muscle health and fitness, especially in the increasing problem of the loss of muscle function with age (sarcopenia).

How does alpha-actinin-3 influence skeletal muscle functions?

Our above research has encouraged us to move towards understanding how the presence or absence of alpha-actinin-3 influences skeletal muscle function. We are doing this in two different ways. One way is to grow skeletal muscle cells in the laboratory which express different parts of alpha-actinin-3 and look at the cell structure change under a microscope. From this, we can obtain information about how each part of alpha-actinin-3 contributes to muscle cell functions. Animal models provide us with the opportunity to further our studies of the effects of alpha-actinin deficiency. We recently created a transgenic mouse model whose alpha-actinin-3 has been taken out to mimic the deficiency of alpha-actinin-3 in a human. Our initial study of this mouse model is very promising.

Selected Publications

Macarthur D, North KN. Genetic influences on athletic performance. Human Genetics 2005, 116:331-339.

Macarthur D, North KN. A gene for speed? The function and evolutionary history of alpha-actinin-3. Bioessays 2004, 26: 786-895.

Yang N, MacArthur D, Gulbin JP, Hahn AG, Beggs A, Easteal S, North KN. ACTN3 genotype is associated with human elite athletic performance. American Journal of Human Genetics 2003, 73:627-631 (Featured in ScienceNews, Genome News Network, Wired News, New Scientist, The Bulletin, Discovery Magazine "Top 100 Science Stories of 2003" - ranked number 76).

Mills M, Yang N, Weinberger R, Beggs AH, Easteal S, North K. Differential expression of the actin-binding proteins, alpha-actinin-2 and alpha-actinin-3, in different species: implications for the development of genetic redundancy. Human Molecular Genetics 2001;10:1335-1346.

North KN, Yang N, Wattanasirichaigoo D, Mills M, Tong HQ, Easteal S, Beggs AH. A common nonsense mutation results in alpha-actinin-3 deficiency in the general population: evidence for genetic redundancy in humans. Nature Genetics 1999;21:353-354.