Myostatin deficiency and gene doping: muscle growth without brakes

Geschatte leestijd: 12 minuten Myostatin is a naturally occurring regulator in the body that limits muscle growth. Inhibiting this function potentially offers enormous possibilities for muscle growth. Myostatin promotes catabolism, breaking down proteins in muscles for energy. Some people have a myostatin dysfunction, resulting in a myostatin deficiency or inhibited function. This can lead to individuals having larger than usual muscles and a predisposition to sports such as weightlifting. In the whole discussion surrounding gene doping, the question is raised whether such individuals should be allowed to participate in competitive sports.

What is Myostatin?

Myostatin was formerly known as Growth and Differentiation Factor 8 (GDF-8) [1]. It is a protein that inhibits the process of muscle tissue formation called myogenesis. This process mainly occurs during embryo growth. Myostatin can also be activated by the use of anabolic steroids [2]. Myostatin is primarily produced in skeletal muscles. It circulates in the blood and works by binding to receptors on muscle cells called activin type 2 receptor [3,4].

Myostatin is an endogenous, negative regulator of muscle growth in determining both the number and size of muscle fibers. Gilles et al. 2007

The myostatin cow

All these difficult words, so let’s quickly take an example of how myostatin works. Better said, an example of what happens when myostatin doesn’t work. Coincidentally, I saw them for the first time “live” a while ago when I was driving through Belgium on my way to France. The “Belgian Blue” cow. An enormously muscular cow of the “Belgian White-Blue” breed. The myostatin in these cows often shows a deviation, preventing its inhibitory effect on muscle growth. This results in excessively muscular cows. Due to selection during breeding, this deviation occurs relatively often. As mentioned, myogenesis mainly occurs during the embryonic phase, and the calves of these cows are already born with extra muscle. A cesarean section is therefore required to give birth to them. This deviation can also occur in other animals such as sheep, rats, and dogs. Above, you see an image of “Wendy the whippet” (whippet = a breed of dog). Wendy also has a mutation of the myostatin gene, making her twice as large as other whippets of the same length and height. In 1997, researchers from John Hopkins University discovered that the mutation in cows (and later it would turn out in other animals as well) was caused by a defective myostatin gene [5].

“Mighty Mouse”

When people of my age and older hear “Mighty Mouse,” they think of the superhero mouse with a cape singing: “Here I come to save the day!”. Mighty Mouse was indeed the name given by researchers at Johns Hopkins University to a mouse with a myostatin deficiency, resulting in it being extra muscular [7]. What’s remarkable about this mouse is that it’s not a natural deviation like the Belgian Blue cows and Wendy the whippet, but a deliberate genetic modification performed by researchers at John Hopkins. It was the researchers at John Hopkins who in the mid-nineties discovered several growth differentiation factors including GDF8 [6], and later the effects of this in Belgian Blue cows [5]. By blocking this gene in mice, they wanted to verify if limiting muscle mass is indeed the biological function of the gene.

To determine the biological function of GDF-8, we disrupted the GDF-8 gene by gene targeting in mice. GDF-8 null animals are significantly larger than wild-type animals and show a large and widespread increase in skeletal muscle mass. Individual muscles of mutant animals weigh 2–3 times more than those of wild-type animals. McPherron et al. 1997

They found that the mice became significantly more muscular after blocking this gene. Their muscle mass increased by about 25% compared to a control group. The mice had stronger and heavier muscles without significant health problems [7].

Inactive myostatin gene

It became clear that an inactive myostatin gene leads to an increase in muscle mass. This discovery quickly sparked a lot of speculation about its possible applications. People with a defect in the myostatin gene could potentially benefit from this in various ways. Besides muscle growth, myostatin has an inhibitory effect on adipose tissue [8], the tissue that stores fat. A higher muscle mass also increases the resting metabolic rate, resulting in a higher energy consumption.

People with mutated myostatin gene

There are people with a mutation of the myostatin gene who have more muscle mass than the average person. In fact, a German boy was discovered who had a defect in both myostatin genes, resulting in a myostatin deficiency. This child is known in the literature as “The Superman Boy.” This child was much stronger than his peers at the age of 4 and had a significantly lower body fat percentage. No known health problems were reported. The parents of the boy were also much stronger than average. Whether this is a coincidence or a consequence of their myostatin deficiency remains unclear.

Myostatin deficiency among bodybuilders and powerlifters?

It was also discovered that there are bodybuilders and powerlifters with a myostatin mutation. A person who has been making the headlines in recent years because of his enormous muscle mass is the Iranian bodybuilder “Sajad Gharibi,” also known as “Iranian Hulk” or “Persian Hercules” [9].

Sajad Gharibi, 24, who is known as the Persian Hercules in his home country, said he is looking for a challenge on the fighting field and wants to compete against the best. Times Now News

There are also many rumors about Arnold Schwarzenegger and his myostatin levels. However, these rumors are unconfirmed. Still, one could imagine that Arnold is a person with myostatin deficiency given his size and strength during his career.

Different types of myostatin mutations

There are many different mutations of the myostatin gene. Not all mutations have the same effect. Some people only have one mutated gene (heterozygous), while others have two mutated genes (homozygous). In general, the more mutated genes, the more pronounced the effect. But this is not always the case. There are also people with two mutated genes who do not have a myostatin deficiency.

Myostatin inhibitor

Myostatin inhibitors are substances that inhibit the function of myostatin. This can be done in various ways. Blocking the myostatin receptor, blocking the myostatin protein, or blocking the myostatin gene. Several pharmaceutical companies are working on myostatin inhibitors. So far, the results in humans are not very impressive, with some muscle growth being the only effect [10].

Gene doping myostatin in animal research

In the world of animal sports, there is also doping. For example, there are stories about Belgian Blue cows being artificially inseminated to increase the chances of a deviation in the myostatin gene. There are also stories about breeding sperm from “Mighty Mice.” Gene doping is still in its infancy but will probably be the doping of the future. Only the future will tell how far we will go to increase performance in sports and how far we want to push the limits of our own health. And with that, I will end this brief explanation about myostatin. I hope I was able to clarify this complex subject somewhat. As always, feel free to leave any comments or questions below. Most is expected in this regard from gene therapy. In this case, for example, by administering a follistatin gene that does its job for years, possibly even lifelong [18]. This is administered by a virus, an Adeno-associated virus (AAV) to be precise. Similarly, the drug Repoxygen ensures that EPO is produced by the muscle cells [19]. Repoxygen is actually a virus with the human EPO gene. This brings us into the realm of “gene doping,” very likely the future of doping in the world of sports. It has been banned by the IOC since 2003 and WADA since 2004). At the last Winter Olympics, it was theoretically possible for the first time to test for gene doping. It is not clear to me whether these tests were actually conducted. Firstly, because there was a debate beforehand about whether it should even be tested for while the added value was not yet clear. Additionally, I am not aware of any cases of people being caught for gene doping. However, it is clear that it is happening. For example, a German TV crew caught a Chinese doctor trying to sell stem cell therapy for $24,000 to a reporter posing as an American swimming coach. Regarding the developments in the field of myostatin: American researchers administered various myostatin inhibitors to mice including follistatin, growth and differentiation factor-associated serum protein-1 (GASP 1), follistatin-related gene (FLRG), and follistatin-344 (FS) [20]. The latter is the variant of follistatin believed to be active only in the muscles.

Here, we describe a one-time gene administration of myostatin-inhibitor-proteins to enhance muscle mass and strength in normal and dystrophic mouse models for >2 years, even when delivered in aged animals. These results demonstrate a promising therapeutic strategy that warrants consideration for clinical trials in human muscle diseases. …Specifically, we show here that follistatin-344 resulted in the greatest effects on muscle size and function and was well tolerated with no untoward effects on cardiac pathology or reproductive capacity in either male or female treated animals. …The striking ability of FS to provide gross and functional long-term improvement to dystrophic muscles in aged animals warrants its consideration for clinical development to treat musculoskeletal diseases, including older DMD patients. -Haidet, The Research Institute, Nationwide Children’s Hospital

The one-time administration of myostatin inhibitors, especially follistatin 344, increased muscle mass for more than two years!

When is gene doping possible and available for humans?

From my perspective, I say: “Hopefully never”. I haven’t worked so long and hard for nothing. As a natural bodybuilder, you can sometimes be envious of guys who are bigger due to anabolic use, but at least they have trained hard and watched their diet alongside the use. In cases where this is not the case, the result is also lacking. With gene doping, however, it seems as easy as pressing a button for muscle mass. Like making an avatar for a game bigger and smaller. Being muscular is then no longer proof of years of dedication. It’s like a tattoo, purely a matter of taste. Being lean also becomes much easier, so the six-pack is no longer special either. However, for the couch potato who is simply too lazy to train and watch their diet but still wants to look muscular, it will sound like music to their ears. The reality is that it cannot be prevented and is probably already being illegally used. There are good medical arguments for the development of such gene therapies. Why spend your whole life on medication to counteract muscle breakdown from a disease when it can be done once and more effectively? Clinical trials are already underway, such as among people with the muscle disease sIBM. FDA approval is likely not far off (21,22). When asked about the timeframe for when gene therapy with follistatin will be available for these patients, the doctors say:

Right now we’re in the middle of the trial, and so far safe and well tolerated. We will have to take the data we collect safety and efficacy data to the Food and Drug Administration and move this forward as quickly and safely as possible. As we don’t have the trial Phase I completed it is hard to set a date or timing, but we will move as quickly and safely as possible to bring this forward if it is deemed safe and effective. – Drs. Mendell and Kasper: Nationwide Children’s Hospital, Columbus Ohio

That’s the formal route. I strongly suspect that illegal use of gene doping has been going on for some time. Bodybuilders are often willing guinea pigs. Just look at the use of dianabol when it was first developed and people had no idea about the side effects. Its inventor (at the behest of Russia), Dr. Ziegler, himself stated that he regretted his invention when more and more people came with liver complaints. The route that must be taken to get a drug approved takes too long for some bodybuilders if they are already convinced of its added value. Especially when, for example, an FDA declares that something can be safely used as a medicine and it becomes available in larger quantities, the path to abuse is open.

Myostatin inhibitors: Supplements or Medicines

It will not be surprising that the supplement industry had already printed labels with “myostatin blocker” as soon as the first studies on myostatin were published. Not strange because as you have read above, inhibiting or lowering myostatin offers enormous possibilities for muscle growth and fat burning. The question is only whether and how supplements achieve this. The word “Supplement” means supplement, in this context, a supplement to the diet. You may wonder whether a myostatin blocker supplement may be called instead of medicine. For many people, something is a supplement as soon as it can be bought in a jar of pills or powder and no prescription from a doctor is required. Unlike a one-time injection with a virus as in gene doping and unlike the use of (injectable) anabolic steroids, a jar of powder will lower the barrier for use for many people. Just look at the large number of people who are tempted by advertisements for supplements that are said to work like anabolic steroids, but do not want to use anabolic steroids themselves. If one can get more muscle growth through daily intake of a pill or powder than through an injection and can stop this daily without side effects and necessary “post-cycle therapy,” then this would be the most popular supplement ever. However, the problem is that oral agents (whether you call them supplements or medicines) often do not have the same effect as injected agents due to the large breakdown that can occur before they reach the bloodstream. The fact that there are (as far as is known) still no really successful injectable myostatin blockers available makes it likely that it will take a while before there are working oral myostatin blockers. This will make a big difference in terms of use. Until now, such so-called myostatin blockers do not work [23] or do work, but the development has stopped due to side effects that need to be further investigated [24,25]. Some should do their work by neutralizing myostatin (such as MYO-029). In another case, a synthetic receptor has been made (ACE-031). As mentioned, myostatin does its job by binding to receptors of the muscle cells called activin type 2 receptor [3,4]. By replicating this receptor and injecting it, present myostatin that binds with it cannot bind with “the real” receptors of the cells. This reduces the effect of myostatin. However, too many side effects occurred in the trials of this drug, leading to the termination of development.

Influence of existing agents on myostatin

Finally, it is good to know that certain agents that we sometimes already ingest can influence myostatin. In reviews of supplements, for example, I often look at the influence of a particular supplement on, for example, testosterone, cortisol, and growth hormone as indicators of a possible positive influence. For myostatin, this can often also be looked at in this way. We may already be reducing myostatin without knowing it through existing food, supplements, or medication. For example, cocoa appears to have an inhibitory effect on myostatin. Or rather, the epicatechin in cocoa [26]. This effect is likely negligible in most cases given the small and varying amount of epicatechin in cocoa. In this regard, there is still plenty of research to be done on myostatin for the coming decades. Rest assured that when injectable myostatin blockers are used for patients and the influence on muscle mass becomes as well known as that of steroids, the supplement industry will list dozens of products that supposedly inhibit myostatin. Just like testosterone boosters are currently being sold, of which I have yet to find one that truly has a significant effect on testosterone.

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