Author's Note:
I am writing this because:
1. It has been the main focus of my physiology research for the past three years.
2. I finally feel competent and confident enough to draw scientific hypotheses from that research.
3. Everyone else is wrong (what a surprise), and it bothers me something terrible.
Introduction
Assuming you are an otherwise healthy adult human of ordinary size and proportion, your athletic potential is almost entirely determined by a single gene. Though many publications have referred to ACTN3 as ["the speed gene", "the sports gene", "the athlete gene", etc.], it is actually much more than that. In this article I will demonstrate that the deletion of this protein from the human genome is not a chance modification spurred on by externalities, but a hard-coded response to specific stimuli.
In part 1 of this article I will provide a background on the gene and its function. I will also cover current scientific theories on the same and dismantle them with ruthless aplomb.
In part 2 of this article I will explore gene-based training methodologies and nutritional planning for humans, both wild and domestic.
Disclaimer: Because I wish to finish this article in this lifetime and have very little time to write, non-controversial background information will be dramatically oversimplified. As always, I urge you to take nothing for granted, and to independently verify anything you question.
Let us begin
In the microscopic world of Chromosome 11 sits a gene to encode the protein Alpha-Actinin-3. On the 577th position of this gene sits either an Arginine (R) or a premature stop codon (X). If there is an Arginine, you can properly encode the protein, if there is a stop codon, you cannot. Because we receive a copy from each parent, it is possible to have 2 copies of arginine (RR), one copy or arginine and a stop codon (RX), or two stop codons (XX).
In fitness we often talk about fast/slow twitch fibers, or even of type I/IIa/IIb/IIx fibers, but there is rarely a dive into what defines a particular type of fiber. Yes, aerobic to the left and anaerobic to the right, but where is the line?
A "fast twitch" muscle fiber usually contains several isoforms of Myosin Heavy-Chain (MHC), Alpha-Actinin-2 (ACTN2), and Alpha-Actinin-3 (ACTN3).
A "slow twitch" muscle fiber contains Myosin Light-Chain, as well as the slower isoform of MHC, ACTN2, and certain structural remodeling proteins not present in fast twitch fibers.
Given this definition, you might think that ACTN3 deficient people have no fast twitch muscle fibers, and you would be correct.
Because ACTN3 deficient people still produce MHC, and all isoforms of MHC can bind to ACTN2, muscular development is severely impaired, but still possible. The resulting musculature (MHC dominant with no ACTN3) has no common name, but I will refer to it as "medium twitch".
ACTN3 deficiency results in smaller, slower, weaker humans with slower recovery and greater susceptibility to injury. This may be why 100% of non-human animals still have two copies of ACTN3. Among humans, ~84% have at least one working copy. I count myself among the 16% who do not. Why has mother nature so forsaken us? First, let us establish why she has not.
The Fury
When I developed my theory of hypertrophy, there was an abundance of research on the topic, the answers to the pertinent questions were just scattered. There were already solid papers on hypoxia, transporter proteins, and sarcoplasmic function, it just so happened that no one else bothered to put it all together.
On ACTN3 there is next to nothing. It was discovered in 1993. A genetic panel was done on two brothers in Sri Lanka who suffered from an uncommon form of muscular dystrophy. Doctors noticed they both lacked ACTN3, and hypothesized that such deficiency was causal (makes me feel great, every time). After testing the seemingly healthy parents (also ACTN3 deficient), that hypothesis was dropped and the world was left to ponder the function of this mysterious protein.
28 years later and the scientific community somehow managed to distance itself even further from the answer. I do not blame the community at large; I owe the diligent scholars of muscle function a great deal in allowing me to develop my own theories. Conversely, I have never seen such lazy, misguided, and contradictory research as I have in searching for an answer to the ACTN3 question. Bad data begets bad data, and the obsession with sarcoplasmic reticulum calcium leak has generated a slew of papers which insist that this single facet of ACTN3 deficiency is not only its defining feature, but its evolutionary prerogative. They are wrong on both counts.
The Acknowledged Facts
1. ACTN3 deficiency causes greater rates of leakage of Ca2+ ions from the sarcoplasmic reticulum. The affects of this are attenuated by similar increases in Ca2+ binding proteins.
2. ACTN3 deficiency causes huge increases in calcineurin during muscle contraction. Calsarcin-2, which would normally bind calcineurin in the presence of ACTN3, is instead bound by ACTN2. The excess calcineurin signals the muscle to adapt aerobically (transition towards slow twitch).
Both of these processes result in more mitochondrial activity, resulting in more ATP being shuttled through the Krebs cycle.
3. ACTN3 deficiency exists primarily in non-African populations.
4. The ACTN3 XX polymorphism appears to exhibit positive selection.
The Worst Theory
Increased leakage of Ca2+ creates a transient state of energy inefficiency, causing an increased rate of muscular contraction, and thus creating a thermogenic effect. Increased mitochondrial activity means more processing of ATP, which also creates a thermogenic effect. Africa is hot. From these facts they theorize that ACTN3 deficiency is an adaptation to cold.
Why They Are Wrong
1. They acknowledge that leakage and reuptake of Ca2+ is mediated by Sarcoplasmic Reticulum Calcium ATPase 1 (SERCA1), but conveniently forget that SERCA1 is a transporter protein expressed preferentially in fast-twitch fibers. They focus on increased SERCA1 expression in ACTN3 deficiency within individual muscle cells without considering alterations in overall thermogenesis by fiber type distribution. A "medium twitch" fiber might express more SERCA1 than an ordinary fast-twitch fiber, but there are fewer of those fibers in ACTN3 deficient individuals. If total thermogenesis between XX/RR individuals is comparable, increased SERCA1 expression would be a compensatory mechanism to ACTN3 deficiency, rather than the reason for it. If total thermogenesis is greater in RR individuals (which I posit to be the case), it would be an incomplete compensatory mechanism.
Translation: A man named XX makes 10 boilers a day in each of his three factories, for a total of 30 boilers. A man named RR makes only 7 boilers a day in each factory, but he owns six factories, for a total of 42 boilers. The man named XX generates more heat per factory, but the man named RR generates more total heat.
2. Increased mitochondrial activity is, by definition, increased efficiency. Researchers will sometimes suggest that ACTN3 was lost due to concurrent "food scarcity" and "cold climate". The argument is preposterous because they ascribe the same functionality of mitochondria to have opposite effects. We are to believe that the additional ATP processing generates excess heat while simultaneously sparing calories.
3. Every study that cites a latitudinal argument is simply bad science. There is NO latitudinal correlation to the presence or absence of ACTN3. Yes, the African Savannah, where nearly every individual has 2 working copies of ACTN3, is close to the equator. So is Sri Lanka, where ACTN3 deficiency was discovered. So is Mexico, where about a quarter of the population is ACTN3 deficient. Every adaptation that occurs outside of the African continent is not a response to cold weather. Large universities and otherwise intelligent researchers proffering the "Africa is hot" hypothesis as an answer to every question is infuriating.
Theory #2
ACTN3 deficiency is correlated with distance from Africa and was positively selected in such populations due to improved endurance and caloric efficiency. This is evidenced by the highest rates of deficiency being observed in indigenous American populations, and the second highest rates being observed in South Asian populations.
My Analysis
It provides a plausible explanation for why the null (XX) variant was positively selected in certain populations, but it says nothing of why it exists to begin with. Accomplishing more work while burning fewer calories is especially advantageous for nomadic peoples, so it is logical that those most suited to travel would travel most. I do not disagree that many high deficiency populations are distant from Africa, but there are also quite a few very close to Africa, such as my own. Thus, it is not "correlated" with distance from Africa, because the rate of deficiency is very high in nearby Italy (~22%), but much lower moving north to Lithuania (~10%) or east to Iran (~11%). Populations far from Africa have higher rates of deficiency, but distance from Africa is not determinative of rate.
Theory #3
ACTN3 deficiency developed as an adaptive mechanism to support novel hunting strategies that coincided with migration away from the wildlife-rich savannah. Chief among these is "persistence hunting", whereby a heat and energy efficient human can pursue a less efficient animal until the animal relents from exhaustion. There are several variations of this theory, but they are all built upon the same foundation, namely the 2004 Bramble & Lieberman article available here: https://scholar.harvard.edu/dlieberman/publications/endurance-running-and-evolution-homo
The premise is that modern humans have undergone a broad series of adaptations which make them uniquely suited to endurance running. The only other mammals with comparable abilities to sustain speed over long distances are wild dogs and hyenas (scavengers). Early ACTN3-deficient man would be better suited to either run other animals to death, or to run efficiently towards already dead animals and compete with other scavengers.
My Analysis
I greatly enjoyed that the above article was focused on biomechanics. From that perspective, it was brilliant and I have no complaints. I cannot, however, agree with its reasoning. There is no evidence that persistence hunting (or scavenging) was widely practiced by early man, and no circumstance to suggest that it should be practiced with greater frequency outside of Africa.
There are several other issues with this theory:
1. Persistence hunting relies on the hunter's comparative advantage in heat dissipation. This advantage is only significant when the environment is hot. Such a strategy would be less effective as humans migrated to colder climates, meaning the adaptation would have occurred only in the populations which have no use for it.
2. The only people (ancient or contemporary) known to regularly practice persistence hunting are the San of Southern Africa. Their ancestors diverged from other African populations about 200,000 years ago, which is about 140,000 years prior to the migration north which would populate the rest of the world. They have been doing it for 200,000 years with two copies of ACTN3. There is no reason to believe that the group which migrated north about 60,000 years ago would biologically adapt to the San lifestyle, when they themselves have found no reason to make such adaptations.
3. East Africans, particularly Nilotic peoples, have evolved to possess most of the known "endurance" genes, as well as mechanically advantageous proportions (long legs, narrow hips, proximal weight distribution). They are inarguably "built" for distance running; no amount of training by athletes from other backgrounds has been able to overcome this genetic advantage. Despite an inordinate number of modifications which favor endurance running, East African populations almost universally possess two functional copies of ACTN3.
Theory #4
ACTN3 deficiency predates migration out of Africa by about 20,000 years, but only underwent positive selection in populations outside Africa. Long runs of homozygosity surrounding the relevant gene indicate that widespread deficiency is the result of population bottlenecks. Basically, ACTN3 deficiency was washed out in Africa because of a large base population, but flourished in migrating populations due to small numbers and inbreeding.
My Analysis
This theory is based on a different calculation than most. We cannot determine the actual age of a single polymorphism, so we derive estimates from algorithms and statistical models. Most estimates place the appearance of the first ACTN3 null gene at about 60,000 years ago. This model places it at more than 80,000 years ago. I disagree with both models, but I will address that later. I see two major issues with this theory:
1. Though there was undoubtedly a population bottleneck (and inbreeding) during the African exodus, successive bottlenecks should exhibit a linear increase in rates of deficiency. The initial Middle Eastern bottleneck should have resulted in less homogeneity than later bottlenecks in the far east. Under this model, it should be impossible that Israel has a higher rate of deficiency (~18%) than Russia (~14%).
2. The importance of the Middle Eastern bottleneck is overstated. While it is true that a proportionately small group of humans migrated out of Africa, the humans that remained did not form a unified social unit. Humans tended to form loose confederacies of no more than 500 members, regardless of their geographical location. More population diversity in greater Africa does not mean more genetic variability within individual societies. If ACTN3 deficiency existed for 20,000 years prior to migration out of Africa, it would still be there.
Discussion: Poor Quality Muscle For Everyone
People misunderstand the function and significance of this gene because they misrepresent it as redundant. If we begin our analysis by assuming the gene is superfluous, or easily discarded for negligible benefits, we are handicapped by bias. It is a very important gene. No other animal on our planet has seen fit to discard it. Without it, we do not have true fast-twitch muscle fibers. We have turned ourselves into softer, slower, weaker versions of our ancestors; easy prey for any predator with a bit of resolve.
Throughout our evolutionary history, we have compromised all of our physical and sensory attributes for the benefit of the brain, and this is no different. Our brains, particularly our prefrontal cortexes, have coevolved with our skeletal muscles. As the two largest consumers of resources, they are engaged in a sort of cold war over the finite (at the time of mutation, anyway) resources. The loss of ACTN3 means smaller, more aerobic muscles, as well as a 50% reduction in glycogenolysis. Efficient muscles that process glucose through the mitochondria, instead of through the wasteful Cori cycle, extract a lot more energy per molecule. A strong shift towards oxidative metabolism saves energy by using fatty acids (even more efficient). Conversely, the brain is now at liberty to engage in more non-oxidative metabolism, capitalizing on the available glucose to create the very same lactate which was denied to the muscles. It even uses the very same monocarboxylate transporters I discussed in my theory of hypertrophy.
Earlier I mentioned that I did not agree with other estimates for the age of the ACTN3 null variant. As tempting as it is to believe that all 16% of us are direct descendants of one guy who had sex with every fertile woman in Egypt some 60,000 years ago, I do not believe it to be true. I think it is of much more recent origin, and that it has arisen in different populations concurrently (though assisted by inbreeding). I had previously sought to tie it to agriculture, as areas of early agriculture have populations disproportionately lacking ACTN3. I cannot definitively state that there is a correlation, however, as the Clovis burial site houses the 12,000 year old remains of a man without ACTN3.
Despite it predating modern
agriculture, it is highly likely to have been influenced by diet. Readily
available sources of glucose, such as fruits and cereal grains would have
proliferated in temperate areas. Positive selection may have been a result of
survivability in a low protein, high carbohydrate environment, which has been
the environment of most humans for most of history. Unless increased lactate
production in astrocytes and decreased lactate production in skeletal muscle
confers an evolutionary benefit in the modern world, I do not anticipate that
positive selection will continue.
I do, however, believe it to be
hard-coded into existing human DNA, regardless of whether the protein is
currently being expressed. Even in populations such as the Maasai and Yoruba, where having two functional copies of ACTN3 is near universal, individual proteins (which do not cause loss of function, unlike R577X) are disappearing. Multiple generations of well-fed and under-exercised
people will cause more spontaneous deletion. If our ancestors’ DNA thought it a
worthwhile tradeoff while animal attack was a leading cause of death, modern
DNA will eventually come around.
We are fast evolving away from our current physical form. Future humans will look somewhat like aliens (grays, if you will) as stereotypically portrayed, with large brains and frail bodies. One can only imagine how boring our sports will become.
So now what? If you are a soft
and doughy man of the future, I will provide guidance on how to retain a
respectable human form. If you are a hard and lean relic of the past, I will
provide guidance on how to make the most of what you have.
