Brave New World

by M. Doug McGuff, M.D.

Recently, Dr. Richard Winett wrote two articles that I consider monumental in the history of strength training and bodybuilding. What makes these articles so amazing is their degree of objectivity and intellectual honesty about a topic that is very easy to delude oneself about. The first article, A Personal Revelation about Set Point Theory can be found in the February, 1998 issue of Dr. Winett's newsletter the Master Trainer. In this article Dr. Winett tells how he was attempting to partially refute the idea of a homeostatic set point. When he actually presented the numbers he had collected over his training career, a different conclusion emerged... "The data strongly point toward some limitations I have in going beyond about 140 pounds of lean body mass. If there is such a thing as a set point as far as producing muscle, my data illustrate that concept." Dr. Winett then goes on to make a startling conclusion... "I'm basically a smaller person and attempts to become bigger have been unsuccessful. These data more strongly confirm that conviction and starkly show that beyond a certain point, I simply seem to gain body fat." Compare these statements of brutal honesty with the usual statement you hear from people in our field such as... "I've gained an inch on my arms, and 2 inches on my chest, and 12 pounds of body weight with only slight decrease in my abdominal definition." What this really means in the light of what Dr. Winett is presenting to us can be translated as... "I've put an inch on my arms and 2 inches on my chest because I've gained 12 pounds of fat." In the April, 1999 issue of Iron Man, Dr. Winett again presents his data with accompanying pictures and asks us Can Accepting Genetic Limitations Be Empowering? In this article Dr. Winett notes... "The unfortunate part is that it took me until I was about 45 to realize, accept and in some ways capitalize on my limitation" and "The irony is that through all my training incarnations I had about the same lean body mass". The greatest testament to Dr. Winett's power of emperic observation is that he made these conclusions about himself before the supporting scientific evidence was known to him. These articles inspired me to keep detailed records of my own progress (recorded workouts, photos and measurements) on a workout by workout basis and they have forced me to similar conclusions. Now there is hard scientific evidence that a muscular set point really does exist.

Myostatin, The Genetic Basis for Muscular Set Point

double-muscled Belgian Blue Observe the photo of the extremely muscular cow to the left. This animal is a double-muscled Belgian Blue bull. Belgium does not have much in the way of sprawling ranch-land so farmers there had to learn to get more bang for their buck. Over the past 30 years, farmers in Belgium were successful in selectively breeding for muscle mass. The mighty Belgian blue has literally double the muscle of an average cow! This cow does not perform any sort of resistance training, he doesn't do HIT, he's never heard of SuperSlow, he doesn't care that an obscure group of people are arguing on the internet about the best way to build muscle. More importantly he has not been treated with steroids. He doesn't know how much money he could make endorsing food supplements. All this guy does to get so massively muscular is stand around and eat grass.

Typically, advancements in any field tend to come from outside the field in question. In our case the answers that we have been asking for so long first came from the field of agriculture, where scientists realized that finding the genetic basis for double-muscling could increase the profit involved in raising beef cattle and other agriculturally important animals. (1).

The first people to isolate the problem was a European team headed by Michel Georges from the University of Liege at Belgium. They found that double muscling is caused by a mutation in the bovine (cow) version of a recently discovered gene that makes a protein called myostatin.(2). Myostatin belongs to the growth-factor beta superfamily, and is expressed specifically in developing and mature skeletal muscle.(3). A specific gene encodes for the transcription of the myostatin protein, which is an inhibitor of skeletal muscle growth. The higher the expression of the myostatin gene, the more myostatin protein is made and subsequently less muscle will be allowed to exist on any given animal. The gene was found by the Georges team to exist on the 2nd bovine chromosome. At about the same time, Dr's Sejin Lee and Alexandra McPherron of Johns Hopkins University had linked mutations in the myostatin to another breed of cattle exhibiting double muscling. This breed was called Piedmontese cattle. Having isolated the gene, Dr's Georges, Lee, and McPherron were able to show that double muscling occurred in these animals because they had undergone a mutation that deleted the gene for myostatin. Just like an albino lacks pigment because he doesn't have the gene that codes for melanin, these animals lack normal regulation of muscle growth because they lack the gene that codes for myostatin. Shortly after this gene was characterized it's exact address was found on other animals such as pigs and mice. The real race was on now, for the person who could develop a technique to "knock out" this gene in normal animals would have a potential landmark discovery. I followed these developments because there were several things that hinted these would have implications to our field.

Possible Implications for Human Muscularity

The first thing that struck me when I saw a photo of the Belgian Blue, is how much it looked like a bovine Dorian Yates. Certain patterns of muscle fiber density produce particular external appearances. The thought immediately was "could the world's best bodybuilders also have the mutation that knocked out the myostatin gene?". Why would these animals look so similar to a top level bodybuilder? It is well known amongst cattle breeders that hypertrophy through exercise is not a profitable way to get more meat on the hoof. Hypertrophied meat is tough and gamey tasting. The less an animal is exercised, the better tasting the beef. Veal is so tender because the calves are kept in a pin so small that they cannot even walk. During the discovery of the Belgian Blue there was concern that their meat might be tough and gamey, but Tim Smith (a pioneer in myostatin research at the USDA) notes that animals with myostatin deletions produce meat "so tender even round steaks fall apart on the grill".(4). It seems that when myostatin is deleted the animals get bigger not because of hypertrophy but because of hyperplasia. These animals simply produce 2 to 3 times as many muscle fibers, all of normal size. So what you say?....If you have a copy of my book Ultimate Exercise-Bulletin 1, turn to page 17. There you will note reference to a scientific study that shows that elite level bodybuilders don't possess bigger muscle fibers, they just possess much greater numbers of small to average sized fibers.(5). Maybe this is true because elite bodybuilders possess the mutation causing myostatin deletion. Everything that I was reading seemed to suggest that one's personal degree of myostatin expression could be determining the limits of their muscular potential, and that the genetic freaks in our sport could have the myostatin deletion. However to reach such a conclusion several other things would have to be shown. First, it would be great to prove that the myostatin deletion is what caused massive muscles, simply showing massive muscles in an animal that has the deletion is not enough...the two facts could be unrelated. We needed to see an animal with a normal myostatin gene have it's gene "knocked out" and then observe the results. Also, it would be nice to locate the gene in humans.

A   B  C

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The Next Step

Shortly after the myostatin gene was identified in cattle, Alexandra McPherron of Johns Hopkins University identified the gene in mice and then proceded to "knock out" the gene in normal mice and see what happened. Observe the photos above to see the astounding results. The photos on bottom are of a mouse that has had the myostatin gene knocked out, the top photos are of a normal littermate (the skin has been removed to better reveal the muscles). The other photo represents a cross section through the hindlimb of a normal and myostatin deleted animal. Mice with the myostatin deletion looked like beady-eyed, furry, little Mr. Olympias. This definitively proved that the myostatin gene was responsible for regulating muscle size and that its elimination would produce double-muscling as seen in the spontaneously occurring mutation.(6). In a personal phone communication with me, Dr. McPherron indicated that identifying the gene and knocking it out is an easy procedure, although any explanation would be way over my head.

Next, I came across a very technical article that I found difficult to understand, but which seemed to suggest that the human myostatin gene was being identified. It seems that yeast artificial clones of the bovine myostatin gene were used to locate and characterize similarities between bovine and human myostatin.(7). Within 3 months of this article I found another article that seemed to describe the human myostatin gene in great detail... "The myostatin gene comprises three exons and two introns, maps to chromosomal region 2q33.2, has three putative transcription initiation sites, and is transcribed as a 3.1-kb mRNA species that encodes a 375-aa precursor protein. Myostatin is expressed uniquely in the human skeletal muscle as a 26-kDa mature glycoprotein (myostatin-immunoreactive protein) and secreted into the plasma. Myostatin immunoreactivity is detectable in human skeletal muscle in both type 1 and type 2 fibers."(8). I had no idea what all this terminology meant but the context of the statement was clear, human myostatin had been isolated to an exact location on the second human chromosome; the protein it produced had been characterized; and its expression in muscle had been isolated. The most amazing thing about this article was that it showed that myostatin definitely regulates muscle size and increased myostatin expression is responsible for muscle wasting in disease states. This study showed that increased myostatin expression is responsible for muscle wasting in AIDS patients. The study concludes "The serum and intramuscular concentrations of myostatin-immunoreactive protein are increased in HIV-infected men with weight loss compared with healthy men and correlate inversely with fat-free mass index. These data support the hypothesis that myostatin is an attenuator of muscle growth in adult men and contributes to muscle wasting in HIV-infected men."(9). If you think about it this makes perfect sense. The HIV virus is a retrovirus that pirates the metabolic machinery of the host in order to produce more of itself. If you you recall in the article The Dose-Response Relationship of Exercise, we pointed out that muscle was the body's most metabolically expensive tissue. It only makes sense that the HIV virus would have some sort of mechanism of upregulating myostatin expression, thereby decreasing muscle mass and leaving more of the body's metabolic energy available to be enslaved for HIV replication.

The Nail in The Coffin

At this point I was confident that myostatin does control muscle mass in animals and humans. It was clear that knocking out myostatin in a normal animal produces double muscling. Experimental evidence shows that increased myostatin expression in humans causes muscle wasting. The evidence seemed to be mounting that world champion bodybuilders might simply be the human equivalent of a Belgian Blue.

This is not to say that champion bodybuilders are not a product of their hard work. In a personal communication with Dr. McPherron I asked to what degree training affected the expression of myostatin. I was told that no human data exists (quantitating changes would require a muscle biopsy), but animal data suggests that myostatin expression can be changed by 20-40% through physical training. However, 20% change in the context of high myostatin penetration is very different than improvements when there is no myostatin inhibition. While a person with a myostatin deletion still gets credit for his work, the accomplishments of a dedicated genetically average trainee are, in reality, equally as profound. When looking at the photo of the Belgian Blue bull (who does no training at all) one must wonder if a human with similar genetic endowment might actually decrease their muscularity if training was improper. I recall the story Arthur Jones tells about former Mr. Olympia Chris Dickerson. Chris was most noted for his outstanding calf development. Arthur made the point that Mr. Dickerson was one of two surviving triplets and that the brother that had never trained actually had calves that were larger than Chris' calves. Recall that maternal twins (or triplets) are actually, in genetic terms...clones. This suggests that all the dedicated training Chris did for his calves only served to make them smaller.

All of these speculations are moot however if we cannot actually demonstrate the myostatin deletion in a human subject. Dr. McPherron was not aware of any documented cases of myostatin deletion in humans, but was very excited about the possibility of finding such a case. I have received consent forms from Dr. McPherron so that I may approach likely candidates for a DNA sample in an attempt to find such a deletion in a human subject. Terry Carter and I have been in touch with likely candidates (who will remain anonymous), and we are hopeful that they will consent to provide a blood sample for DNA testing. The research world is not interested in this from a bodybuilding or cosmetic standpoint. Characterizing this mutation in humans may hold the key to the cure for various forms of muscular dystrophy, as well as potential treatment of muscle wasting associated with HIV, cancer, and aging.

Personally, I was hopeful that I might be one of the first to show interest in finding a human example of the myostatin deletion. During an extensive literature and internet search of the topic I came across an astounding article. It appears that a gentleman named Victor Conte, President of a company called BALCO Laboratories, Inc. has been testing for the myostatin gene in champion athletes. It seems that champion bodybuilder Flex Wheeler has tested positive for the myostatin deletion. Here is a quote from the article:

"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."(10)

This article, if published in a peer reviewed scientific format, will certainly be the "nail in the coffin" proof of what we in the H.I.T. field have known emperically for a long time: extreme responders are much more a product of their genetics than the particular training regimine they espouse. Their superior ability to pack on muscle may be enhanced by training and/or steroids but most certainly has nothing to do with the various supplements which they endorse. While such "champions" are genetically exceptional, that does not necessarily make them exception people who are deserving of the kind of hero worship that suggests they achieved what they have because the are more dedicated than the average trainee. Indeed the accomplishments of most genetically average trainees may equal or exceed that of an extreme responder when viewed in light of our knowledge about myostatin.

The Morning After

After discovering what I felt was fairly definitive evidence for a genetic basis of a muscular setpoint, I had very mixed feelings. After sharing this information with Terry Carter, we both seemed to settle into a malaise that lasted for several days. For the first time in 18 months we missed a workout together. Later, the realization that we had found hard evidence for what we knew all along seemed to provide a sense of liberation. The most amazing thing we pondered was the astounding metabolic efficiency of the body. Evidence collected by us, as well as HIT enthusiasts everywhere, shows that strength gains continue long after size gains grind to a snail's pace. Many other significant issues are raised by this knowledge. Below is a partial list. I'm sure you will come up with more of your own.

1. In light of their genetic endowment, the results of top bodybuilders may not be as impressive as we once thought. Our own achievements as subjects with more normal myostatin expression might actually be more impressive when viewed in the proper context.

2. The current rage about supplements and pro-hormones is largely marketing hype. Endorsements from top bodybuilders should be highly suspect, as should their recommendations for training. Magazines that are essentially marketing tools for supplement companies should be recognized as being similar to women's fashion magazines; offering up genetic freaks as the physical ideal and offering products that promise to make you look like them....yeah, right!

3. The current "religious wars" going on within the HIT field are not nearly as important as we think they are. The differences produced by subtle nuances of good solid HIT philosophy are like pissing in the ocean when compared to the influence of an individual's myostatin gene. Training should consist of good ,basic HIT, performed in the safest manner possible, within the constraints of recovery. Emphasis should be on gradual, long term progression.

4. Like Dr. Winett so eloquently points out, knowing our limits will allow us to free up our attention so that we may focus on more productive improvements, such as becoming leaner.

5. Hopefully, more top bodybuilders will present themselves for myostatin testing. This will give admirers a more realistic picture of what can be achieved. More importantly, characterizing the DNA sequence of those possessing a myostatin deletion may hold clues to the cure for certain types of muscular dystrophy as well a muslce wasting diseases.

6. As more data is collected, maybe a databank can be established that correlates and quantitates myostatin expression to training expectations. With such data a trainee could know what to expect from the outset and be able to monitor where he is on the journey. Perhaps it could also be used as a screening tool to find what form of sport one might be best suited for.

7. Perhaps within our lifetime, one might be able to delete or down-regulate the expression of their own myostatin gene, selecting the degree of muscular potential they find desirable. This is unlikely, as it is potentially dangerous in fraught with ethical dilemmas...but wouldn't it be cool?

8. Most importantly, I hope this liberates our thinking so that we can pay attention to the other benefits of high intensity strength training. While building muscle has always been our primary goal, it really is just the "tip of the iceberg" of what H.I.T. has to offer. Our muscles are literally our window to the body. The physiologic support systems of the body can only be accessed by performing mechanical work with the muscles. The more demanding the muscular work, the more profound the physiologic adaptations. The Tabata protocol is a much more effective cardiovascular workout than traditional aerobics precisely because the muscular work is more severe. Eventually, the world will come to realize that properly performed H.I.T. is even more effective than the Tabata protocol. Proper H.I.T., especially the SuperSlow protocol, is (in my opinion) superior for cardiac rehabilitation for reasons I will discuss in future articles. Dr. Phillip Alexander at Texas A&M Medical School is collecting some impressive data on the effects of SuperSlow on lipid profiles and other health parameters. In the 21st century we will come to realize that H.I.T. is much more than building muscles.

Further Information

New research on myostatin is still ongoing. We at Ultimate Exercise will be following these developments closely. We will also be involved in collecting DNA samples from subjects likely to possess the myostatin deletion. Consent forms for those wishing to participate should be available soon. Study participants will receive $100.00 for their participation. Please call us if you have a likely candidate. For those wishing to discuss this article or discuss the latest information we are aware of on this subject you may do so by scheduling a phone consultation. Call (864)886-0200 for rates and appointment times.


Bibliography

1. Gene Mutation Provides More Meat on the Hoof. Science, Vol. 227: September 26, 1997.

2. Ibid.

3. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muslce mass in mice by a new TGF-beta superfamily member. Nature 1997 May 1;387(6628):83-90.

4. Gene Mutation Provides More Meat on the Hoof. Science, Volume 227: September 26, 1997.

5. Alway, S.E. et al. Contrasts in muscle and myofibers of elite male and female bodybuilders. J. Appl. Physiol. 67(1):24-31, 1989.

6. Gene Mutation Provides More Meat on the Hoof. Science, Volume 227: September 26, 1997.

7. Sonstegard, T.S. et al. Refinement of bovine chromosome 2 linkage map near the mh locus reveals rearrangements between the bovine and human genomes. Anim Genet 1998 Oct; 29(5):341-7.

8. Gonzalez-Cadavid, N.F. et al. Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting. Proc Natl Acad Sci USA 1998 Dec 8;95(25):14938-43.

9. Ibid.

10. Conte, Victor. Web page posting. http://www.musclephotos.com/myogene.html