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A common nonsense polymorphism (R577X) in the ACTN3 gene results in complete deficiency of the fast skeletal muscle fiber protein α-actinin-3 in an estimated one billion humans worldwide. The XX null genotype is under-represented in elite sprint athletes, associated with reduced muscle strength and sprint performance in non-athletes, and is over-represented in endurance athletes, suggesting that α-actinin-3 deficiency increases muscle endurance at the cost of power generation. Here we report that muscle from Actn3 knockout mice displays reduced force generation, consistent with results from human association studies. Detailed analysis of knockout mouse muscle reveals reduced fast fiber diameter, increased activity of multiple enzymes in the aerobic metabolic pathway, altered contractile properties, and enhanced recovery from fatigue, suggesting a shift in the properties of fast fibers towards those characteristic of slow fibers. These findings provide the first mechanistic explanation for the reported associations between R577X and human athletic performance and muscle function.
Here’s a report in the popular press….
Related: Run long, run short…..
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“.. the mutant form of the ACTN3 gene ..arose during the last ice age and rapidly increased in Europe and Asia thanks to natural selection”: what was it about Eurasia that made greater demands on endurance? Something to do with the winters?
Those data don’t look so great to me. I’d guess that alpha-actinin-2 (the other muscle-specific actinin) can compensate for some of the loss of 3. I wonder what the double knockout would look like phenotypically.
I have a longish comment on this thread that I guess has been caught in a moderation queue – any suggestions on how to get it out?
the problem are links. if you want something posted, email it to me.
Thanks razib – I’ll try again.
Disclaimer: I’m an author on this paper.
bioIgnoramus: The quote from the news article about arising in the last ice age is a bit dubious. In reality the selection events could have begun anywhere between 10 and 50,000 years ago, but they’re certainly more recent in Europe than East Asia.
We don’t think selection was on endurance capacity per se (although I guess that’s possible). More likely the increased muscle metabolic efficiency provided resistance to famine, or maybe there’s some impact on cold tolerance. Eurasia obviously provided plenty of novel environmental challenges – we’re still trying to figure out which was the major player in this case.
Kris: yep, there’s definitely compensation from actinin-2. In our last paper (in Nature Genetics) we showed that actinin-2 is up-regulated in the KO mouse and shifts its expression to take over where actinin-3 goes missing. In humans actinin-2 is already expressed in all muscle fibres, so we think it plays a compensatory role there too.
Knocking out actinin-2 would almost certainly result in embryonic lethality since it’s the sole isoform in the heart. We have collaborators working on a muscle-specific KO as we speak.
Can you spell out exactly which “data don’t look so great” to you? Bear in mind those are 95% CIs on the histograms, not SEMs. Some of the phenotypes are certainly subtle – but that’s really what we expected, given the mild phenotype in human “knockouts” (20% of the population!).
Hey Mesk, thanks for your replies.
We’ve been doing a bit of work on Actinins in zebrafish. Specific to this discussion, we’ve found that there are two Actn3s that appear to both be expressed. It doesn’t appear that only one of those copies has been selected for function, as is the case with many of the gene copies created during the teleost genome duplication however many millions of years ago, where one copy eventually accumulates enough mutations and becomes a psuedogene and transcriptionally silent.
We’re going to be publishing (relatively) soon, as soon as some more in situs get completed, and it really will not be much more than a survey of Actinins in the zebrafish with a bit of functional analysis for Actn1 (I just injected some dom neg RNA this morning), but it is interesting to consider (and this is something we’ll probably include in the handwaving, uh, I mean discussion section, of our paper a comparison between fish and mammalian muscle and metabolic requirements for Actn3.
It’s interesting that there appears to have been at least some constraint against losing the extra Actn3 in zebrafish (possibly all teleosts), while human populations seem to be under strong selective pressure to develop more slow-twitch, slow-metabolism musculature.
The expression pattern between Actn2 and Actn3s during early zebrafish development is interesting in that their expression domains are (as near as we can tell so far) mutually exclusive, which was a bit unexpected.
Question: What are the population genetics of these runner-muscle genes? Europeans vs. Africans vs. Asians, for example?
The “endurance” version of the ACTN3 gene has a low frequency (~10%) throughout most of Africa, and a higher frequency (~50%) pretty much everywhere else (Europe, Asia, the Middle East, Oceania), with some variation.
ben, also, pubmed is handy for there sorts of questions. e.g.,
http://www.ncbi.nlm.nih.gov/SNP/GeneGt.cgi?geneID=89
(though alfred is a bit more user friendly)
The “endurance” version of the ACTN3 gene has a low frequency (~10%) throughout most of Africa, and a higher frequency (~50%) pretty much everywhere else (Europe, Asia, the Middle East, Oceania), with some variation.
Fun. So am I right to read this as a strong argument against those who say Ethiopians are the winners of long-distance running competitions because of those claimed African long-distance running genes?
ben, also, pubmed is handy for there sorts of questions.
thanks. “So You Want to Be a Population Geneticist” is tagged for later reading.
So am I right to read this as a strong argument against those who say Ethiopians are the winners of long-distance running competitions because of those claimed African long-distance running genes?
It’s a strong argument against ACTN3 playing a major role in the dominance of east Africans in endurance events. We’ve tested this directly: comparing east African controls and athletes there’s no significant difference in ACTN3 allele frequencies (although we had reduced power due to low allele frequency).
That’s very different from saying that the east African dominance doesn’t have any genetic component – it’s pretty clear that it does.
Aug: very interesting work. I’ve sent your post to a colleague who’s doing some phylogenetic analysis of the actinins, including in zebrafish. We’ll be in touch. 🙂
Mesk:
Fair enough. I guess the relevant question is how much of the variance in endurance running ability does ACTN3 account for?
The studies to test that directly haven’t been done yet. However, for muscle strength and sprinting performance in non-athletes ACTN3 explains around 2-3% of the variance, so it’s probably of that order of magnitude (actually probably slightly less) for endurance running.