actinin-3, including reduced muscle strength and increased
endurance performance.
It’s important to note that no single gene can be used to
determine our athletic ability. Like many physical features,
athletic performance is a complex characteristic that involves
both our genes and the environment. There are likely to be
many genes that contribute to athletic performance, but α-
actinin-3 was the irst for which a clear association has been
demonstrated in many athlete and non-athlete groups.An Adaptation to Cold?
By studying α-actinin-3-deicient humans and the ACTN3
knockout mouse, signiicant progress has been made in under-
standing how ACTN3expression alters muscle function. This
has led to an appreciation of the diverse roles that α-actinin-3
plays in our skeletal muscle. But how did this variation become
so common in modern humans?
The ACTN3gene is estimated to be over one million years
old. However, the genetic signatures surrounding the ACTN3
R577X variant suggests recent positive selection for the loss of
α-actinin-3 as modern humans migrated out of Africa into
colder climates around 15–30,000 years ago. This means that
the number of people who possess the R577X allele is at its
highest in places with reduced mean annual temperature and
food availability. This suggests that the R577X allele may have
conferred resistance to cold exposure or famine.
R577X is one of only two known examples in the human
genome where a gene variant results in a clear selection advan-
tage. (The other is a variant in the CASP12gene, which inlu-
ences our ability to resist serious infection).
As such, there is great interest in understanding how α-
actinin-3 deiciency provides an advantage and why the absence
of this protein alters human muscle function today. We have
already shown that the loss of α-actinin-3 appears to be detri-
mental to sprint/power performance but may beneit muscleendurance. The current theory for this increase in α-actinin-3
deiciency is that a shift towards slower muscle ibres that use
energy more eiciently provides a survival advantage during
exposure to cold and famine.Muscle Diseases
It is now well established that ACTN3inluences performance
in elite athletes, but the ultimate goal of our laboratory is to
ind cures for children suffering from severe muscle diseases.
Recently we have started to explore how ACTN3inluences
the severity and progression of diseases associated with muscle
weakness.
To understand the effect of α-actinin-3 in muscle develop-
ment and disease we examined our ACTN3knockout mouse
in response to muscle disease. Using a method that is similar to
prolonged bed rest in humans, which results in muscle wasting
over time, we examined how wild-type and ACTN3knockout
mice responded to immobilisation. Interestingly, we were able
to show that α-actinin-3 deiciency protects against muscle
breakdown in response to immobilisation. ACTN3knockout
mice resisted muscle wasting compared with wild-type controls.
Currently we are building on the knowledge we have gained
by studying elite athletes and the ACTN3knockout mouse to
determine the role of α-actinin-3 in inherited muscle disorders
such as Duchenne muscular dystrophy, as well as muscle-wasting
conditions seen during ageing some types of cancer. We propose
that the changes in muscle strength and metabolism induced
by ACTN3will inluence the way individuals respond to and
develop different disease conditions.
Australia has a fantastic track record in the science of sport
performance, and it would be great if we can build on that
knowledge to help ind new treatments for inherited muscle
diseases and wasting conditions.
Peter Houweling is Senior Research Officer at the Murdoch Childrens Research Institute,
where Kathryn North is Group Leader and Director.26 | MAY 2016
A world map that shows the
proportion of 577X (red) and
577R (blue) alleles in the local
populations. The 577X allele has
increased as modern humans
migrated out of Africa (red
arrows) into the colder Eurasian
climate. The mechanism for this
change is yet to be determined
but may be due to resistance to
cold, famine or increased
endurance performance.Resistance to coldResistance to famineEndurance capacity?