The α-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, α-actinin-2 and α-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 α-actinin-3 is absent (deficient) in the skeletal muscles of more than one billion people world wide. The absence of this protein is due to a “mistake” in the gene encoding α-actinin-3 which changes the amino acid Arginine (R) to an early terminator (X).  This mistake subsequently creates two forms of the α-actinin-3 gene in human: R (normal) and X (deficient).

The absence of α-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. In 2003, we collaborated with the Australian Institute of Sport, and investigated α-actinin-3 deficiency in a group of Caucasian athletes. By comparison to the general Australian Caucasian population, in whom the frequency of α-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 α-actinin-3. In the mean time, we also found that α-actinin-3 deficiency rate in endurance athletes are slightly higher (~28%) than in the general populations. We therefore became the first group in the world to show it is important for athletes to have α-actinin-3 to perform in sprint events and it may be beneficial to have no α-actinin-3 in endurance events. In support of our findings, two research groups in Finland and Greece reported recently the similar results from studies of their elite athletes respectively.

Since publishing our athletes study, α-actinin-3 deficiency has been found to influence skeletal muscle functions in non-athletes. In collaboration with scientists in Glasgow University Scotland this year, we found that α-actinin-3 deficiency reduces sprint speed in adolescents. Without α-actinin-3 in skeletal muscles, two other research groups found that adult females have less base-line strength, and older people respond to strength training differently.

All studies conducted so far point out that α-actinin-3 deficiency changes how the muscle contracts. We asked ourselves how this is happening and whether the changes have any impact in human health. In order to address these questions, we took an approach to generate a genetically modified mouse whose α-actinin-3 gene has been taken out to mimic the deficiency of α-actinin-3 in a human, the α-actinin-3 knock-out mouse.

Intriguingly, our knock-out mice run longer than normal mice before reaching exhaustion. After in detail analysis, we find the contraction of skeletal muscles changes to slower in speed, and α-actinin-3 deficiency results in muscle that is essentially "pre-trained" for endurance performance. This, in principle, explains why α-actinin-3-deficient humans are beneficial to endurance events while performing more poorly in activities requiring muscle strength or rapid power generation. Further analysis confirms that this is due to energy metabolism in muscles shift towards more energy efficient oxidative pathway. These data, together with our evolutionary history analysis of α-actinin-3 gene, will be published in the top journal Nature Genetics soon.

Animal models provide us with the opportunity to extensively study the effects of α-actinin-3 deficiency. We now have set up our long term gaols to investigate the consequences of α-actinin-3 deficiency in a wider range of skeletal muscle health and fitness, especially in the increasing problem of the loss of muscle function with age (sarcopenia).