Fast or Slow? Long or Strong?
Our skeletal muscle consists of two α-actinin proteins, α-actinin-
2 and α-actinin-3. While it was originally thought that these
proteins provide structural support to our muscles during
contraction, we now know that they interact with many different
proteins that have structural, metabolic and signalling roles.
Functional differences in these pathways have been identiied
in α-actinin-3-deicient muscle, and these differences combine
to alter muscle function.
α-Actinin-3 is predominately expressed in the fast-twitch
ibres of our skeletal muscle. These ibres are responsible for
rapid and forceful contractions but they fatigue quickly and
are prone to injury. This is the opposite of our slow-twitch
muscle ibres, which generate less force but are resistant to
fatigue.
The R577X variant plays an important role in our muscles’
ability to generate strength. Through changes in muscle struc-
ture, metabolism and cellular signals, people who are α-actinin-
3-deicient have a shift in their fast-twitch muscle ibres towards
the properties of a slower muscle ibre. Therefore α-actinin-3-
deicient muscles generate less power during contractions but
recover more quickly from fatigue.
Deiciency of α-actinin-3 does not cause muscle disease, but
is a natural variant that inluences muscle function and perform-
ance.
Athletes Are a Breed Apart
In 2003 we examined 439 elite Australian athletes and 436
unrelated controls to demonstrate that the loss of α-actinin-3
is detrimental to sprint performance in elite athletes. In this
study the number of α-actinin-3-deicient sprint/power indi-
viduals was signiicantly lower in both male and female sprinters,
with no Olympic sprint athlete being α-actinin-3-deicient.
This landmark study has now been repeated in at least 15
independent studies of athletes from around the world. To
date, no elite sprint athlete has been found who is α-actinin-3-
deicient. On the other-hand, α-actinin-3 deiciency was found
to be higher in female Australian endurance athletes.
In addition, the R577X variant also inluences normal muscle
function in non-athletes. Both men and women deicient in
α-actinin-3 show reduced muscle strength and take longer to
complete timed sprints. These indings are consistent with the
athlete data, and suggest that α-actinin-3 deiciency has a detri-
mental effect on sprint/power performance and potentially
beneits endurance sports.
In order to study the loss α-actinin-3 in more detail we devel-
oped an ACTN3knockout mouse that doesn’t expresses α-
actinin-3 in its skeletal muscle. While the knockout mice look
the same as their wild-type littermates, we observed clear differ-
ences in muscle function and metabolism.
ACT 3knockout mice generate less force but run further
on a motorised treadmill, mirroring the performance of α-
actinin-3-deicient human muscles. Knockout mice also show
a shift in the metabolic characteristic of their muscles.
Given the speciic expression of α-actinin-3 in fast ibres,
the functional effects on sprint and endurance performance
and the interaction between the α-actinins and many meta-
bolic proteins, we investigated whether the loss of α-actinin-3
produced changes in skeletal muscle metabolism. We exam-
ined the two principal metabolic pathways in skeletal muscle:
anaerobic metabolism (predominantly fast-twitch muscles)
and the slower, more eicient aerobic metabolism predomi-
nantly found in slow-twitch muscles.
The data indicated a shift in the muscle metabolism of
ACTN3knockout fast ibres away from their traditional reliance
on anaerobic metabolism to the aerobic metabolism of slow-
twitch muscles.
We have also begun to identify the molecular switches that
cause these changes in muscle strength and metabolism. In
2013 we demonstrated that calcineurin activity – a key signalling
protein that inluences the fast-to-slow skeletal muscle ibre
type change – is higher in the absence of α-actinin-3. We believe
this drives many of the features associated with the loss of α-MAY 2016|| 25k k l f b f hStaining reveals the different muscle fibres in the quadriceps
muscle of a mouse: blue (type I), red (type II) and black (type
IIx/a)fibers. The muscle fibre boarders are green.αα-Actinin-
3 is specifically expressed in the type II (red) muscle fibres.