α-Actinin and Skeletal Muscle Performance

In 1999 our group found that α-actinin-3 is absent (deficient) in the skeletal muscles of more than one billion people worldwide. 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 humans: 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 meantime, we also found that α-actinin-3 deficiency rate in endurance athletes are slightly higher (~28%) than in the general population. 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 lack α-actinin-3 for performance in endurance events. In support of our findings, five other international research groups have since reported similar results from studies of their elite athletes.

Since publishing our athletes study, α-actinin-3 deficiency has also been found to influence skeletal muscle function in the general population. In collaboration with scientists in Glasgow University Scotland, we found that α-actinin-3 deficiency reduces sprint speed in adolescents. Two other research groups showed that without α-actinin-3 in skeletal muscles adult females have lower muscle strength and that older people respond to strength training differently.

All studies conducted so far point out that α-actinin-3 deficiency changes how 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 generated a genetically modified mouse whose α-actinin-3 gene has been removed to mimic the deficiency of α-actinin-3 in humans, the α-actinin-3 knock-out mouse.

Intriguingly, our knock-out mice run longer than normal mice before reaching exhaustion which fits with our finding in the athletes that it may be beneficial to lack α-actinin-3 for performance in endurance events. After in detail analysis, we founds that the contraction of the muscles in the knock-out mice is slower, and that α-actinin-3 deficiency results in muscle that is essentially “pre-trained” for endurance performance. This, in principle, explains why α-actinin-3-deficiency appears to be beneficial to endurance performance.  Furthermore, if the muscle in α-actinin-3 deficient individuals is specialised for endurance then this could also explain why these individuals appear to be performing more poorly in activities requiring muscle strength or rapid power generation. Further analysis confirmed that the energy metabolism in α-actinin-3 deficient muscles shift towards more energy efficient oxidative pathway. These data, together with our evolutionary history analysis of α-actinin-3 gene, were published in the journals Nature Genetics and Human Molecular Genetics.

We extended these initial studies of α-actinin-3 deficiency in a number of ways. We investigated the metabolic changes in α-actinin-3 deficient muscle in more detail and found that the activity of the enzyme glycogen phosphorylase was lower. We proposed that changes in the activity of this enzyme contribute to the other metabolic changes (the shift towards energy efficient oxidative metabolism). We also looked at the effects of α-actinin-3 deficiency on muscle ageing and found differences in the way that muscles deteriorate with age in the α-actinin-3 deficient mice. Additionally, we have shown that α-actinin-3 deficient muscle is more susceptible to contraction induced damage.