It’s theorized in the bodybuilding community that the reason Flex Wheeler and other top Olympia caliber bodybuilders are able to build such incredible physiques is due to Myostatin deficiency.
Other popular theories circulate around that include ideas as vastly different as androgen receptor sensitivity is higher in top bodybuilders, to the complete opposite side of the spectrum where some believe that training past a certain pain threshold is what separates champions from the rest and that genetics are just a small factor in determining bodybuilding success.
In this article I delve into Myostatin gene mutations, claims about top Mr. Olympia bodybuilders' DNA, and outline what kind of potential impact Myostatin has shown to have in the clinical data.
In addition, I take a deep dive into the actual study conducted on Flex Wheeler and a handful of other Mr. Olympia contenders and show what was revealed about their DNA, as well as how it compared to average individuals.
Myostatin Gene (MSTN) and Its Role in Myostatin Production
Before delving into a real-world example of a purported Myostatin deficiency in humans (Flex Wheeler), I'm going to get into the gene a bit itself.
The MSTN gene is a gene that makes instructions for producing the protein myostatin.
Myostatin regulates skeletal muscle growth by restraining it when necessary.
In turn, it prevents the body from gaining too much muscle.
Current research that surrounds myostatin is based around its treatment for musculoskeletal degenerative diseases.
Coincidentally, animals that have mutations in the encoding gene MSTN show greater muscle mass, strength, and in some circumstances reduced body fat as well.
Examples of Myostatin deficiencies are found in lab based rodent models, as well as in the farming industry with myostatin deficient cattle.
Myostatin Knockout Mice
Mice that lack the gene that creates myostatin have approximately twice as much muscle mass as normal mice [R].
Myostatin inhibitors have been proposed by many to be the most promising new area of science in a bodybuilding context, as well as potentially better alternative treatment for muscle wasting diseases.
Belgian Blue Double-Muscled Cattle
The Belgian Blue has a myostatin gene mutation, consequently preventing its feedback loop of muscle growth inhibition from working correctly.
This mutation interferes with fat deposition and can lead to accelerated lean muscle growth.
The acceleration of muscle growth in Belgian Blues is due primarily to physiological changes in the animal's muscle cells (fibers) from hypertrophy to a hyperplasia mode of growth.
This growth occurs in the fetus and results in a calf being born with two times the number of muscle fibers as a calf without a myostatin gene mutation [R].
Myostatin Elevates In Response To Androgens
While there are likely other counterregulatory mechanisms in the body that inhibit excessive muscle growth, the main factor appears to be myostatin elevation.
Myostatin increases to prevent you from gaining unhealthy amounts of muscle.
In the following study, the effects of exogenous testosterone and trenbolone on myostatin levels was evaluated [R].
This study showed that after 29 days of administration of either testosterone or trenbolone, myostatin protein levels were 197% higher in the castrated and testosterone group, and 209% higher in the castrated and trenbolone group when compared to the placebo.
There's a reason why this mechanism is in place in our bodies and we can't grow linearly.
Too much of anything is not going to be good, and when you try to push your body to a place that isn't healthy, homeostatic mechanisms in the body will try to stop you.
The human body is a big balancing act.
More Androgens = More Myostatin = More Muscle Growth Inhibition
As previously outlined, myostatin is a growth inhibitor that elevates in the presence of androgens.
Based on the current research it appears that the higher your dose of exogenous anabolics, the greater muscle growth potential you have, and consequently the higher your myostatin will elevate in parallel to inhibit absurd rates of muscle growth.
In a study evaluating the effect graded doses of testosterone have on myostatin levels in young and older men, myostatin levels were significantly higher on day 56 than baseline in both groups [R].
The myostatin hypothesis isn't air tight and has some holes in the data contradicting its muscle growth inhibiting effects.
However, based on what we know to date, the research suggests that its more than likely the main regulatory mechanism involved in muscle growth response relative to androgen receptor activation.
Myostatin is well known to negatively regulate muscle mass in mice, cattle, dogs and humans [R].
Myostatin Is Elevated In HIV Positive Individuals
Myostatin is detectable in human skeletal muscle, and its expression is increased in the muscles of HIV-infected men with muscle wasting compared to that in normal men [R].
Does this mean that the muscle wasting that occurs with disease is caused in part by myostatin elevation?
Maybe, and the relationship between the two is definitely notable.
Studies Measuring How Much Myostatin Gene Mutations Can Affect Bodybuilding Progress
A small study was conducted to discover if the mutations in the SNP rs1805086 have any impact on the male bodybuilding population from a muscle hypertrophy and muscle performance standpoint [R].
The secondary aim was to speculate if rare mutations are more prevalent in those who decide to choose a sport such as bodybuilding, as research indicates that mutations in MSTN can illicit larger muscle mass gains and a reduction in body fat.
The Lys(K)153Arg(R) polymorphism in exon 2 (rs1805086, 2379 A>G replacement) of the myostatin (MSTN) gene is a candidate to influence skeletal muscle phenotypes and is listed on SNPedia as the top risk genotype for causing myostatin-related muscle hypertrophy [R, R].
17% of the subject group had one mutation (AG), 83% had the common outcome (AA) and 0% (0) had two mutations (GG).
Those with the AG genotype had an average arm circumference of 46.37 cm compared with AA which had an average of 42.02 cm.
Those with the AG genotype had an average pull-up max score of 21 compared with AA with an average of 12.
Those with the AG genotype had an average push-up max of 61 compared with AA with an average of 40.
The study clearly shows that those with a mutation are rare, however the mutation does appear to give the subject a performance and size advantage over those with the common outcome.
Another study had similar findings when evaluating A55T and K153R polymorphisms [R].
Our results indicated that individuals with AT + TT genotype of the A55T polymorphism showed a significant increase in the thickness of biceps (0.292 ± 0.210 cm, P = 0.03), but not quadriceps (0.254 ± 0.198 cm, P = 0.07), compared to carriers of AA genotype.
For the K153R polymorphism, the increases in the thicknesses of both biceps (0.300 ± 0.131 cm) and quadriceps (0.421 ± 0.281 cm) were significantly higher among individuals with KR than those with KK genotypes (P < 0.01 for both muscles).
The results obtained therefore suggested a possible association between the two polymorphisms and the strength training-induced muscle hypertrophy among men of Han Chinese ethnicity.
The K153R polymorphism is the same Lys(K)153Arg(R) polymorphism in exon 2 (rs1805086, 2379 A>G replacement) of the myostatin (MSTN) gene evaluated in the first study mentioned.
According to SNPedia, these 3 SNPs definitely relate to myostatin-related muscle hypertrophy:
|Max Magnitude||Chromosome position||Summary||RiskGeno||NormalGeno|
The rs1805086 SNP in particular is the one most commonly looked at in relation to bodybuilding outcomes.
It is often referred to during discussions of the “bodybuilder gene”.
The rs1805086 SNP genotype AA is seen as the commonly occurring one, with the risk alleles being the rs1805086 GG genotype.
The disease literally listed as a potential outcome of having this risk genotype is myostatin-related muscle hypertrophy.
Just having one G allele is rare to begin with, and being homozygous for it is very rare.
In my first video, I was basing my conclusion of Flex Wheeler's genetic significance solely off the extrapolation of Victor Conte's broad statement in his letter.
I assumed that Flex probably had the rarest GG genotype for the rs1805086 SNP.
However, after digging into the study conducted on Flex Wheeler itself, we are led to what is likely a much different conclusion, and is what I will delve into next.
Flex Wheeler Myostatin Deficiency
Supposedly, Flex Wheeler was a participant in a study conducted in collaboration with the department of human genetics at the university of Pittsburgh involving 62 men.
During this study, Flex was purportedly found to have a very rare myostatin mutation at the exon 2 position on the gene.
In theory, this supposed gene mutation prevented his body from producing normal amounts of myostatin, consequently resulting in a much larger number of muscle fibers than the average male.
Animals and humans with inhibited myostatin levels have consistently shown to have much greater levels of musculature relative to their non-inhibited counterparts, and based on this it isn't crazy to assume that genetic freaks in bodybuilding developed their physiques as a result of a similar gene mutation.
In theory, someone with low myostatin levels could continue to progress at rates that would be impossible for someone with normal myostatin levels.
The end result of chronically low myostatin levels could potentially be substantially greater levels of muscle gain from the exact same diet, training and drugs.
Victor Conte's Letter About Flex Wheeler
Victor Conte is one of the individuals associated with the myostatin mutation study conducted on Flex Wheeler and an assortment of other IFBB pro bodybuilders.
99% of those in the bodybuilding community who discuss Flex's myostatin deficiency are referencing a letter written in October, 1998 by Victor Conte.
Whether this letter is legitimate and unaltered is unclear, but for what it is worth, we will assume it is legit as it is what has circulated around our community for years.
October 1, 1998
Re: Flex Wheeler
To whom it may concern:
I am writing this letter per the request of Flex Wheeler.
I would first like to briefly provide you with some background information regarding BALCO Laboratories. BALCO has been working with elite Olympic and professional athletes for over fifteen years. BALCO has provided testing and consultation for over 250 NFL players including the entire 1998 Super Bowl Champion Denver Broncos team and the entire Miami Dolphins team. BALCO works with professional athletes in many sports including tennis (Michael Chang, Jim Courier, etc.), hockey, bodybuilding (10 of the 16 1998 Mr. Olympia contestants), track and field, soccer and basketball (Seattle SuperSonics).
BALCO Laboratories has been testing and monitoring Flex on a routine basis during the last year. We have performed tests including blood chemistry (SMAC), complete blood count (CBC), PSA, anabolic hormone levels, genotyping as well as comprehensive testing for nutritional elements. Flex's test results have been compared to twenty-four other professional bodybuilders and overall he has one of the healthiest profiles. Basically, Flex is in excellent health and has demonstrated the discipline necessary to maintain a peak level of conditioning.
Flex was a participant in a study we recently conducted in collaboration with the Department of Human Genetics at the University of Pittsburgh involving 62 men who made unusually large gains in muscle mass in response to strength training (extreme responders). Flex was one of only nine extreme responders that had the very rare “myostatin mutation.” Myostatin is the gene that “limits muscle growth.” Specifically, Flex had the rarest form of myostatin mutation at the “exon 2” position on the gene. This simply means Flex has a much larger number of muscle fibers compared to the other subjects or the normal population. We believe that these are the very first myostatin mutation findings in humans and the results of this landmark study have already been submitted for publication. Flex was also found to have a very unusual type of the IGF-1 gene. In fact, Flex was the only participant in the study that did not have a “match.” All of the other extreme responders had at least three other subjects with a matching IGF-1 gene. Based upon Flex's very unique genetic profile, we plan to expeditiously publish a scientific paper that reveals his complete genotype in specific detail. The publication of his remarkable genetic data should generate an enormous amount of media exposure.
Hope this information will be helpful and please call if I can be of assistance.
/s/ Victor Conte
BALCO Laboratories, Inc.
The Myostatin Mutation Study Conducted On Flex Wheeler And Other IFBB Pros
This study is commonly referenced but I have yet to see someone actually dig it up and cross reference the data in it with the statements made in Victor Conte's letter.
I did some digging and found it.
The study is called “frequent sequence variation in the human myostatin (GDF8) gene as a marker for analysis of muscle-related phenotypes” [R].
Based on what Victor stated in his letter, there were nine extreme responders with a very rare myostatin mutation.
Supposedly Flex Wheeler had the rarest mutation of all at the exon 2 position on the gene, making him unique from all other individuals in the study.
Subjects In The Study
Sequencing of selected regions of the myostatin gene and genotyping of common variants were carried out in a comparison sample of 96 randomly selected Caucasian and 96 African American subjects from the general population.
An additional 72 individuals were screened for a common exon 2 variant.
One hundred fifty-three subjects, including 127 men (32 African American, 91 Caucasian, and 4 Asian) and 26 women (9 African American, 16 Caucasian, and 1 Asian), were categorized by the magnitude of increases in muscle mass they experienced from strength training.
The subjects consisted of:
- 18 world-class bodybuilders (ranked in the top 100 worldwide)
- 25 competitive bodybuilders not ranked in the top 100
- 7 elite power lifters
- 9 university football players
- 55 previously untrained subjects who had their quadricep muscle volume measured by magnetic resonance imaging before and after 9 weeks of heavy resistance strength training of the knee extensors
- 61 nonathletes, who were questioned about their ability to increase their muscle mass in response to intense and prolonged strength training
5 of the 18 world-class bodybuilders were Mr. Olympia contenders ranked in the top 10 worldwide.
A rating of 5 was given to those who were world-class bodybuilders and to those who increased their quadriceps muscle mass by more than 400 cm³ after only 9 weeks of strength training, whereas a rating of 0 was given to those who experienced no noticeable increase in muscle mass after vigorous strength training for at least 6 months.
Eighteen subjects received a rating of 5, and 13 subjects received a rating of 0.
The ratings of the remaining subjects fell somewhere between these two extremes.
62 subjects who were rated as either 4 or 5 were classified as extreme responders, and were compared to 48 subjects who were rated as either 0 or 1 and were classified as nonresponders.
Subjects were also grouped and compared by race.
Information on muscle mass changes with strength training from the remaining subjects was obtained through either estimates of fat-free mass assessed by dual-energy X-ray absorptiometry or hydrodensitometry or in the case of competitive bodybuilders, power lifters, football players, and nonathletes, through questionnaire data on prior success in bodybuilding competition and/or reported changes in muscle mass with strength training.
Without boring you with the less relevant details in the study, the most notable part is the conclusion.
The lack of a significant relationship between myostatin genotypes and overall muscle mass response to strength training suggests that response is not significantly influenced by variation at the myostatin locus.
However, it is interesting to note that three of the African American nonresponders were homozygous for the less common (Arg) allele at the exon 2 K153R site, while none of the responders were homozygous for this allele.
Three of the five mutations causing the double muscle phenotype in cattle occur in exon 2 and are recessive, but two are chain termination mutations and one is a deletion, expected to produce a nonfunctional myostatin protein.
Whether variation in the myostatin gene influences muscle phenotypes other than the muscle mass increase in response to strength training requires further exploration.
The less common Arg allele that is being referred to in the study conclusion is the mutation that you would expect Flex Wheeler to have.
But, it doesn't appear that he has it.
Sandwiched in the middle of the study is a mention of what may be highlighting the true root of Flex's genetic superiority.
Among the six nucleotide changes, two, P198A and the intron 2 A/G, were observed in a single individual and two, I225T and E164K, were observed in two individuals, always heterozygous with the wildtype allele.
The remaining two were present in the general population as common polymorphisms.
The (A55T) and (K153R) variants are common in both ethnic groups, with the less frequent allele having a three to four times higher frequency in African Americans.
These variable sites have the potential to alter the function of the myostatin gene product and could alter nutrient partitioning in individuals heterozygous or homozygous for the variant allele.
What we can presume Flex Wheeler has is two nucleotide changes, P198A and the intron 2 A/G.
That is the only note in the entire publication that distinguishes one individual in the study from the rest.
What we can presume to be the nucleotide changes Flex Wheeler has aren't even mentioned on SNPedia's list of related risk genotypes.
The only vague reference we have to it is in a study that examined the association between the MSTN exonic variants and ‘explosive’ leg power in 214 male university students [R].
And in that study the only thing mentioned is that no subjects in the study had the MSTN exonic variant P198A.
It appears that despite the uncommon (Arg) allele at the exon 2 K153R site being the main focus of most Myostatin papers and being honed in on as the root of the “bodybuilder gene”, it does not seem to have as significant of an impact on muscle growth response to training as many thought at the end of the day.
The lack of a significant relationship between myostatin genotypes and overall muscle mass is very notable as this study included 5 Mr. Olympia caliber bodybuilders, and several other top tier IFBB pros.
The most interesting thing to note is that three of the African American nonresponders were homozygous for the less common (Arg) allele at the exon 2 K153R site, while none of the responders were homozygous for this allele.
Of the identified GDF8 variations in humans, the Lys(K)153Arg(R) polymorphism in exon 2 (rs1805086, 2379 A>G replacement) of the myostatin (MSTN) gene is a candidate to influence skeletal muscle phenotypes [R].
None of the extreme responder bodybuilders were homozygous for this allele though.
I had mentioned in the first video that having the AG genotype in general is rare.
It was found to have a significant impact on muscle size and muscle strength in the study I outlined earlier in the article.
Logically, you would assume that the GG genotype (which is even more uncommon), would result in a lack of myostatin and some insane level of muscle growth.
That doesn't seem to be the case though based on this study.
3 of the subjects who had a poor response to training and subpar muscle growth (nonresponders) were the ones who had this rare genotype.
Only three individuals had extremely rare nucleotide changes.
This includes who I assume to be Flex who has two nucleotide changes, P198A and the intron 2 A/G, and two other individuals having I225T and E164K nucleotide changes, all of which were heterozygous with the wildtype allele.
That leaves 2 top tier Mr. Olympia caliber bodybuilders, several other world class IFBB pro bodybuilders, and a lot of other elite athletes, with MSTN genotypes that have shown to have minimal impact on muscle growth response to training in this study.
The two other nucleotide changes causing the double muscle phenotype in cattle are the A55T and K153R variants and are present in the general population as common polymorphisms.
These variable sites have shown potential to alter the function of the myostatin gene product and could alter nutrient partitioning in individuals heterozygous or homozygous for the variant allele.
However, the data in this study shows that there is not a significant relationship between myostatin genotypes and overall muscle mass response to strength training.
Inconsistencies In The Clinical Data And Victor Conte Letter
I don't know where the statements in the letter Victor wrote are coming from.
He claims that Flex Wheeler had the rarest form of myostatin mutation at the exon 2 position on the gene.
But when we look at the study itself, it says 3 of the non-responders were homozygous.
None of the responders were homozygous.
Flex Wheeler would have undoubtedly been categorized as an extreme responder, and yet, he was not one of the individuals with the GDF8 variation in humans we would expect to see in a myostatin deficient individual.
Based on this, we can presume he is the individual mentioned in the study with two nucleotide changes, P198A and the intron 2 A/G.
Victor also mentioned how “nine extreme responders had the very rare myostatin mutation.”
We can see in the data that only three individuals had uncommon nucleotide changes, not nine, and the rest of the subjects had common polymorphisms present in the general population.
In addition, of the mutations mentioned, even if more of the top caliber bodybuilders had notable mutations, the study conclusion still states that there is not a significant relationship between myostatin genotypes and overall muscle mass response to strength training.
Victor also stated in his letter that Flex is one of the healthiest of his professional bodybuilders he's been monitoring, and that Flex is in excellent health.
We have performed tests including blood chemistry (SMAC), complete blood count (CBC), PSA, anabolic hormone levels, genotyping as well as comprehensive testing for nutritional elements.
Flex's test results have been compared to twenty-four other professional bodybuilders and overall he has one of the healthiest profiles.
Basically, Flex is in excellent health and has demonstrated the discipline necessary to maintain a peak level of conditioning.
This was written on October 1, 1998.
If you know the history of Flex Wheeler, you'll know that he ended up having to stop competing after discovering in 1999 that he had focal segmental glomerulosclerosis (a form of kidney disease), and then retired shortly thereafter.
I don't know how something that massive could be overlooked to that extent.
It makes me question the legitimacy of this letter in the first place.
If Flex was truly on the brink of kidney failure, I don't see how it was determined that he was one of the healthiest bodybuilders being supervised by Victor, and how this extensive testing didn't pick this up.
The first thing that comes to my mind is curiosity around whether or not there was some sort of money-making endeavor associated with this.
The supplement industry was crazy in the 90's.
Steroids were sold legally over the counter, and you could make ridiculous false claims about pretty much whatever you want and then sell products based on that.
The false claims are still around today, but now we have the resources at our fingertips to actually see through the garbage being marketed to us, whereas in the 90's nobody knew better and a myostatin inhibiting supplement that can make you as jacked as Flex Wheeler likely would have sold like crazy.
Maybe this guess is way off of what the real intention was, but I don't see what could have been the motivation behind this letter, or what it was seeking to accomplish.
It is entirely possible that they were thinking of teaming up to create some sort of myostatin inhibitor supplement that would be based on Flex's unique genotype.
I don't know if the further publication that Victor mentioned in the letter ever came to surface.
Based upon Flex's very unique genetic profile, we plan to expeditiously publish a scientific paper that reveals his complete genotype in specific detail.
The publication of his remarkable genetic data should generate an enormous amount of media exposure.
I'm assuming that this was probably put on the back burner after Flex had his health issues in 1999.
I don't know what the goal of this letter was, and there are several inconsistencies between it and the actual study that would need further clarification to make any conclusive statements.
Who was this letter addressed to and why was Flex Wheeler requesting this letter be written in the first place?
Aside from the mystery of this letter that greatly interests me, it seems like we can at least conclude based on the study findings that most myostatin gene mutations do not appear to be the differentiating factor between top Mr. Olympia caliber extreme responders and the average joe.