In the history of the supplement industry, there have been thousands of products produced that promised to help you get that muscular body you’ve always wanted. In this long history, there have only been a handful of Big Ones. By Big Ones, I mean products that have changed the face of the industry, literally rocked it to its foundation, and revolutionized the way most of us think about supplementation.

Creatine, MRPs, and ephedrine/caffeine based fat burners all fit into this category. New developments, like MAG-10, are also causing industry wide shockwaves as companies that thought they were on the cutting edge suddenly realized they were old news. The supplement industry literally changed overnight, and that ain’t no hype.

So everyone wondered what could possibly be next. Surely, there’s nothing left to invent and nothing innovative left to discover. The boundaries have been reached! Yeah, and that’s probably what horse drawn carriage makers said right before the automobile hit the market.

Enter the myostatin binder, CSP-3. Don’t even try to fit it into your previous understanding on how supplements work. Wipe your slate clean. This is going to require a whole new paradigm. If this new category — the Myostatin category — of supplement works as expected, it will not constitute a new chapter in the history of supplements, but a whole new book.

To better understand this new category, we decided to talk to Dr. Tim Ziegenfuss and Dr. Stephen McGregor. In addition to Tim Patterson, these are two guys who probably know more about this new supplement than any other person on the planet.

Chris: Okay, let’s start with the basics here, guys. When a person starts training, he adds muscle very quickly. After several years, this slows down and soon he’s lucky if he adds a few lean pounds a year. Why? What is it in the body that limits muscle growth?

Dr. Ziegenfuss: Muscle growth is controlled by the interplay of many factors. Excluding diet and training, the most important genetic determinants of muscle growth are probably anabolic hormone levels, androgen and GH receptor number/sensitivity, muscle fiber type, muscle fiber architecture (the arrangement of fibers) and most recently, myostatin levels. As we move toward our individual "genetic ceiling" of strength and size, these factors become more and more important in determining the rate and magnitude of strength and size gains.

Dr. McGregor: Well, that’s a rather complex question, and as Tim said, the true reason is likely multi-factorial. If you asked ten different muscle physiologists that question, you would likely get nine different answers and one "no comment."

Let’s assume that myostatin might be a factor involved in this diminished response scenario. At the molecular level, regulation of the myostatin gene is controlled by a lot of the regulatory mechanisms that are responsible for contractile protein accumulation and muscle growth. In other words, the more muscle you accumulate, the stronger the signal for myostatin to be expressed. This makes sense from a physiological standpoint, as most of our physiological systems are based on feedback mechanisms to maintain homeostasis.

So, if pre-training muscle mass is your homeostatic set point for muscle, the farther away from that set point you get, the stronger the feedback signals are going to be. So, as you build more muscle, you’re getting farther away from your homeostatic set point, and the myostatin signal might be one aspect of the feedback mechanism intended to resist the tendency to get farther away from the set point.

Chris: Biotest and Pinnacle have both developed products that contain a myostatin binder, called CSP-3. So what is CSP-3 supposed to do as far as taking the limits off muscle growth?

Dr. Ziegenfuss: That's right. Pinnacle manufactures CSP-3 under the name "MyoZap," and Biotest manufactures CSP-3 under the name "Myostat." Both are the exact same ingredient, though.

Anyway, CSP-3 is a very specific polysaccharide that's found in a cultured strain of sea algae, called Cystoseira canariensis. In a nutshell, we know from chromatography experiments that CSP-3 binds to myostatin very tightly, even more so than heparin. Because it’s already been established that myostatin controls changes in muscle fiber size/number, our goal is to competitively inhibit the myostatin protein in vivo. If we can do that with CSP-3 (even partially), the end result could be a dose-dependent increase in muscle mass.

Chris: Interesting. What’s your take, Steve?

Dr. McGregor: Well, as I understand it, this compound has been demonstrated to bind myostatin using biochemical techniques. If it does indeed bind myostatin, we can draw analogies to the effects that have been demonstrated using another myostatin binding compound, follistatin. Follistatin is a normally occurring hormone in mammals that has been demonstrated to bind myostatin also. If you add follistatin, at sufficient concentrations, to in vitro cultures of muscle, the growth inhibitory effects of myostatin are negated.

In transgenic mice that over-express follistatin, pectoralis muscle mass is 50 to 100% greater than older, more fully grown, mutant mice that express non-functional myostatin receptor (ACTIIB). These ACTIIB mutant animals, in turn, have pectoralis muscles that are 50 to 100% greater than normal controls. Most people are familiar with the pictures of the Piedmontese bulls that exhibit a mutant myostatin gene. Well, if you bred bulls that over-expressed a myostatin inhibitor like follistatin, they would likely be even bigger.

Chris: Okay, mice with great pecs and bulls with big honkin’ sirloins. Now, where does myostatin binding come in?

Dr. McGregor: It appears as though the most effective way to minimize the growth inhibitory effects of myostatin is to use a myostatin binding compound. This is likely because there are other cytokines similar in structure to myostatin that possess growth and myogenic inhibitory properties of their own, and there’s likely some binding and inhibition of these factors as well. So, the primary muscle growth inhibitory factor in these studies is likely myostatin, but some other factors that inhibit muscle growth might also be bound and neutralized as well.

Chris: Okay, I’m aware there’s a myostatin gene and there's a myostatin protein. What do we need to know about that?

Dr. Ziegenfuss: As Tim Patterson mentioned in his article, The Myostatin Project, the myostatin gene regulates the production of the protein, but it’s the protein that’s thought to be responsible for limiting muscular growth. And as it turns out, the myostatin protein can be measured in blood and is negatively correlated with changes in lean mass, i.e. as myostatin goes up, muscle mass goes down and vice-versa.

Dr. McGregor: Well, that goes back to my last point. In transgenic animal studies, or in the Piedmontese bull, the mutant myostatin gene exists at conception. Genes are certain sections of DNA that ultimately code for functional proteins. If a gene is turned on, it expresses the protein that then exerts an effect. So, in the case of the Piedmontese bull, the myostatin gene will get turned on during fetal development in an effort to stop muscle cell proliferation, so the baby doesn’t grow out of the mother’s womb.

The gene is mutated though, so the protein that’s expressed isn’t functional and the muscle cells continue to proliferate until some other factor causes them to slow down or stop. The end result is a baby bull that has a lot more muscle cells than the angus in the next pen.

The same sequence of events goes on in the human fetus as well. So, if a future bodybuilder is fortunate enough to have a mutation in the myostatin gene, he’ll be born with more muscle cells than the average Joe, predisposing them to greater muscle mass gains with training.

Chris: Does myostatin come into play after we’re born?

Dr. McGregor: Yes. There’s a reserve population of baby muscle cells — satellite cells — that are present in our muscles. When we train or injure a muscle these satellite cells are activated to proliferate in response to the trauma of training or injury. The myostatin protein will be expressed by the surrounding tissues to make sure the satellite cells don’t proliferate too much, thus limiting the proliferative response.

But, if you can bind the protein, it’s conceivable that the satellite cells will proliferate longer before becoming mature muscle cells that will fuse to existing muscles, thus enabling them to get bigger.

Chris: So we’re not talking about "turning off" a gene here, but limiting what it can do?

Dr. Ziegenfuss: Exactly. Anyone who says they can alter the genome with a dietary supplement is either a liar or a politician… wait, that’s the same thing.

Dr. McGregor: Well, I’m not going to cast aspersions and call anyone a politician, but no, I don’t believe such products are going to "turn off" genes; that would be a far more complicated task than any one product could perform, and they’re not going to result in mutations in the genes that would resemble the genotypes of the Piedmontese bull.

You’re right though, by binding the myostatin, you’re endeavoring to attenuate what the protein does, or ideally, negate its effects.

Chris: Explain it to me like I’m ten years old and have Attention Deficit Disorder. What is difference between hyperplasia and the proliferation of new muscle cells?

Dr. McGregor: Hyperplasia is considered an increase in the number of intact mature muscle fibers. This happens during fetal development to establish the number of muscle fibers we’ll be born with. It may also happen to a small extent post-natally. In animals, in particular birds, using some experimental models, this has been demonstrated in adults also. It doesn’t likely happen to a great extent in adult humans though.

Proliferation is simply cell division of rudimentary cells that’s usually a transient event. In the fetal-development example I used, proliferation of the myoblasts would occur during the process of hyperplasia. In the adult though, mature muscle fibers can’t proliferate or divide. The baby muscle cells though, the satellite cells, do proliferate when activated by trauma or strength training. In this process the satellite cell is activated, moves to where it’s needed to repair the injury or strengthen the muscle, then divides once, or a few times, to provide more cells for the repair.

Some of the daughter cells will go back to that reserve state of being a satellite cell, while others will begin the journey toward being a full-blown muscle cell. This process is referred to as differentiation in general, and when talking about muscle cells, it’s typically called myogenesis.

Chris: Thank you, Captain Encyclopedia. Now, these gains from taking a myostatin binder are touted as being permanent. Explain that to me.

Dr. Ziegenfuss: If we assume that binding myostatin can increase muscle-fiber number, yes. Just like adipocytes (fat cells), once new muscle cells are formed they are there for the duration. And while muscle-cell size and contractile characteristics will vary according to diet, training status, etc., their number remains constant. Until we reach retirement age, that is, when for reasons not yet understood we actually lose muscle fibers — mostly fast twitch! But as Dr. McGregor will surely point out, binding myostatin may also induce hypertrophy of existing fibers… and in this case, size gains would be contingent on an adequate training stimulus.

Dr. McGregor: Well, the comparison that comes to mind is steroid use. The primary mechanism that results in muscle growth with steroid use is artificially enhanced protein synthesis. Although there’s some evidence that some steroids do activate satellite cells, it’s likely such activation would be subject to myostatin inhibition. So, without substantial satellite cell proliferation contributing more nuclei to the existing muscle, when you remove that artificial stimulus for protein synthesis, the muscle reverts to its size prior to use. This is based again on homeostatic mechanisms that are in place to keep us near our muscular set point.

In the case of myostatin inhibition, though, the primary mechanism of muscle growth is likely increased satellite cell proliferation. It will still be necessary to activate satellite cells to proliferate through strength training, but once activated, they’ll proliferate more, thus contributing more nuclei to the mature muscle. Once there are more nuclei in the muscle, the protein synthesis doesn’t need to be artificially elevated. And as long as there’s no severe inactivity, the gains may be permanent.

Chris: What about myostatin’s effect on hypertrophy?

Dr. McGregor: That’s another thing to think about. Although most people have been concentrating on the effects of myostatin on satellite-cell proliferation, there’s some evidence that indicates that myostatin gene inhibits not only muscle-cell proliferation, but hypertrophy as well.

That means that binding the myostatin gene could possibly result not only in muscle-cell proliferation, but some muscle-cell hypertrophy as well. That, however, still needs to be proven.

Chris: Let's get back to this hyperplasia thing. Inhibiting myostatin won't pack on pounds of muscle overnight, meaning you'd need to give the new muscle cells some time to develop, correct?

Dr. Ziegenfuss: Absolutely. Without getting too technical, the process necessary to promote muscular growth from inhibiting myostatin involves a series of steps at the cellular level that take time (i.e., satellite cell activation/proliferation -> myoblast proliferation -> myotube formation -> mature muscle cell formation).

Dr. McGregor: Well, this is sheer speculation, but if you subscribe to the school of thought that myostatin inhibition in the adult will result in enhanced satellite cell proliferation, the effects would likely take some time; certainly longer than say prohormones or steroids.

The time frame for satellite cell activation, proliferation, fusion and contribution to hypertrophic response would be in the order of weeks. So, it would depend on how effective you were at activating your satellite cells. The cumulative effect of continually having more satellite cells proliferating and contributing to the mature muscle could be substantial.

On the other hand, if binding myostatin leads to muscle cell hypertrophy, too, the gains may be a little faster. I think we’ll have to wait on anecdotal evidence for the answer to that one.

Chris: So, over time, you could conceivably gain a substantial amount of muscle mass by inhibiting myostatin. But how long before the average guy will notice the benefits? And will he "feel" anything?

Dr. Ziegenfuss: Assuming that CSP-3 works in vivo the way we think, you’re talking at least a month (maybe longer) before any measurable effects are likely to occur. In the transgenic animal studies to date, it has taken about eight weeks to see changes in muscle mass. And that’s from mutations in the myostatin gene itself. Since we’re fooling with the myostatin protein, it could take even longer.

Relative to "feeling" anything, my hunch is the average guy probably won’t feel jack because the process is so slow. Remember, CSP-3 isn’t a stimulant and isn’t known to affect the central nervous system, so don’t expect that "superhuman" feeling that accompanies the use of some thermogenics and androgens. We’re tackling a completely different animal here.

One point of clarity, though, in my opinion, an average guy with reduced levels of androgen and GH mRNA might notice greater improvements in muscle mass than those lucky ducks who tend to gain muscle at the drop of a hat.

Dr. McGregor: The best way to guesstimate a timeline for something like this would be to use muscle injury models as a comparison. The primary mode of regeneration following severe muscle trauma is satellite-cell activation, proliferation and fusion to the injured muscle. Following severe injury, recovery is typically complete in mice by two or three weeks. In less severe models in humans, a similar timeline has been observed.

Hypertrophy following satellite activation won’t occur until the cycle of differentiation and fusion has been completed. So, if satellite cells are activated, hypertrophy from those cells will likely not happen prior to three to four weeks. Observable hypertrophy? It’s hard to say. I certainly wouldn’t expect anything in less than a month.

With myostatin inhibition, I doubt if the individual would feel anything. Myostatin doesn’t exhibit any neuro-inhibitory effects that I know of.

Chris: What side effects or risks are involved with CSP-3? Will binding myostatin affect cardiac muscle?

Dr. Ziegenfuss: Although I’ve heard some scientists speculate that inhibiting myostatin might lead to increased heart size (cardiac muscle does contain small amounts of myostatin), I’m not buying it, and here’s why:

First, in contrast to sheep and cows, human myostatin appears to be uniquely expressed in skeletal muscle as a 26-kDa glycoprotein. And second, even in gene-knockout models where myostatin is rendered completely inactive, pathological growth of organs isn’t typically seen.

Dr. McGregor: Cardiac muscle does express myostatin following injury, but this is because the gene is present in heart muscle and a lot of the factors that regulate cardiac muscle growth are similar to skeletal muscle. Cardiac muscle doesn’t have satellite cells though. Since mature muscle cannot proliferate, the effects of myostatin would be moot.

During cardiac development, myostatin may play a role though as presumptive cardiac muscle cells are proliferating. This wouldn’t be affected by an adult using an effective myostatin binder, though. Further, I’ve seen no reports in the literature of altered cardiac function in myostatin or follistatin mutants.

Chris: So to appease those worried about trying something so new, tell me this: Are you taking it yet? If not, will you be?

Dr. Ziegenfuss: Of course, there are no guarantees, but let me put it this way: with three kids and a wife, I’m no great risk taker, but I’m currently using 1000 mg/day of CSP-3 as part of my "get ready for summer" training program.

Dr. McGregor: I live in Michigan, so the sled dogs haven’t gotten here with my shipment yet. But I wouldn’t see any problem in taking such a supplement.

Chris: Should CSP-3 be taken on a bulking or a cutting phase?

Dr. Ziegenfuss: That’s a good question. I can think of three reasons to consider using MyoZap or Myostat during a bulking phase: One, inhibiting myostatin causes hypertrophy of fast twitch muscle fibers. Two, inhibiting myostatin may also cause the formation of new fibers via hyperplasia. And three, inhibiting myostatin can increase "lean growth efficiency" meaning, given the same amount of calories and protein, more muscle is gained.

On the other hand, using CSP-3 during dieting might also be an excellent way to "keep the muscle and lose the fat." This is particularly true for trainees that have a dietary fat phobia that causes their endogenous Testosterone levels to hover around the low end of the normal range. From what we know now, less "T" typically means more myostatin… and that ain’t good for gaining (or keeping) muscle.

Along the same vein, we all know what excessive stress can do to muscle. In this regard, glucocorticoids have been shown to upregulate myostatin expression, and this is probably one reason why we turn into worthless bags of atrophy when we let work, school, or a new girlfriend interfere with regular training: cortisol goes up, myostatin increases, and muscle mass declines.

Chris: Tim Patterson mentioned a study in Part 2 of The Myostatin Project which showed that animals with lower myostatin levels have anywhere from 33 to 50% less body fat, regardless of diet. Does that mean this supplement could lead to body-fat loss as well as the formation of new muscle?

Dr. Ziegenfuss: Actually, the body fat loss Tim mentioned refers to isolated areas on the animals (i.e., epididymal, inguinal and retroperitoneal fat pads). When researchers looked at total body fat, they found a 70% decrease in myostatin-null mice compared to normal mice. Similar body recompositioning effects have also been shown in cattle and in genetic models of obesity where animals are genetically altered to be obese.

So in animal models, yes, inhibition of myostatin appears to cause substantial fat loss. Whether or not these effects will occur in humans is, of course, currently unknown. But if you pin me down and make me guess, I’d expect any potential decrease in body fat from MyoZap or Myostat to be overshadowed by potential gains in muscle.

Dr. McGregor: Well, you may not like my answer on this one. Again, this is only speculation, but I think this is an artifact of the genetic manipulation having an effect during development. You may not know this, but during embryonic development, muscle cells and fat cells come from the same parent cell population. So, if you’re allowing the muscle cells to proliferate to a greater extent during development you’re likely limiting the ability of fat cells to form. So, when the individual is born they simply have less fat cells and more muscle cells.

I could end up being wrong, though. We’re learning that there’s an extensive endocrine and paracrine network that’s composed of other cytokines (leptin comes to mind) that results in communication between skeletal muscle and fat cells. So, it may be that myostatin may have some growth promoting effects on post-natal fat cells, and myostatin inhibition would result in reduced growth of fat during a bulking phase. Most of the info on myostatin and fat is pretty new. Geez, myostatin was just identified in 1997, so we still have a lot to learn.

Chris: Any special workout that would complement this product well? There’s been some talk about using slow eccentrics with a good stretch.

Dr. Ziegenfuss: Although hypothetical, it’s not too much of a stretch (no pun intended) to think that regular activation of satellite cells would lead to greater/more rapid gains in muscle mass. And in my opinion, training that emphasizes eccentric muscle contractions fits the bill perfectly.

Basically, the goal during CSP-3 supplementation should be to induce systematic, progressive ultrastructural damage to the muscle fibers. So in this case, the adage "no pain, no gain" applies. But because of recovery/overtraining issues, you’d probably need to keep the volume low and rotate that type of training among body parts from week to week.

One idea I’ve been toying around with is manipulating diet, supplement use, and training to bring up weak body parts. Not to give away any secrets, but this would involve maintenance work (and no or limited supplementation) for body parts that grow easily, and the opposite for stubborn body parts.

Dr. McGregor: The immediate thought might be to do heavy eccentrics to activate the satellite cells, and that might be a good idea, but I wouldn’t rule out some other approaches. The problem with heavy eccentrics is that they’ll still elicit muscle injury and damage through proteolysis and inflammation. I would certainly stretch. In some other work I was involved in, we found that stretch elicited some of the physiological responses associated with eccentric contractions, without inducing the injury. So, non-contractile stretch might activate the satellite cells and then a traditional hypertrophy workout would provide the stimulus for continued proliferation.

Chris: Fascinating stuff. How about diet when using Myostat or MyoZap? Is it like steroids where people have to eat tons more protein?

Dr. McGregor: Any time you’re going to increase protein accretion you need to eat more protein. So, I’d say yes, you’d want to eat more. A ton more? I’d err on the side of eating more than less.

Dr. Ziegenfuss: As I mentioned earlier, some animal literature shows that myostatin inhibition can increase "lean growth efficiency," meaning that given the same diet the critters synthesized more lean mass and less fat mass. Logically, if Myostat or MyoZap increases muscle mass, extra calories (and protein) will be necessary to sustain it. How much extra? I have no idea, but would guess it would be dependent on the amount of muscle gained.

Chris: Any point in "loading"?

Dr. McGregor: That’s hard to say. We don’t know much about the pharmacology of this compound yet, so I really don’t know.

Dr. Ziegenfuss: Not from what I can tell.

Chris: How about stacking Myostat or MyoZap with anabolic compounds?

Dr. Ziegenfuss: Again, although completely theoretical, stacking CSP-3 with androgens and GH boosters (if you can find any that work) might accelerate the muscle building process. But as my colleague Lonnie Lowery and I are fond of saying, supplements should be the icing on the cake — not the cake itself. In other words, sound training and a good diet should be the cornerstone of any serious physique seeker… but the readers of T-mag already know that!

Dr. McGregor: Like I said before, there’s some evidence that some steroids may help activate satellite cells. If this is the case, then there might be a combined effect by using an effective anabolic compound with a myostatin inhibitor. Not necessarily synergistic, but the effect would likely be greater than without the anabolic compound.

Chris: Thanks for talking to us today, guys.

Man, that’s a lot of info to digest, so here’s a brief summary:

• CSP-3 (Myostat or MyoZap) might literally take the "governor" of muscle cell growth, leading to new, previously unseen gains.

• It may take a few weeks to see results, but unlike steroids, the results may be permanent.

• CSP-3 does not affect heart muscle.

• Heavy eccentric workouts might work best while "on" and workout time could possibly be increased without causing overtraining.

• Might aid in fat loss.

• Should work in both bulking and cutting stages.

• There are no know negative side effects.

• Stacks well with androgens like steroids or MAG-10.

• The mechanism is non-hormonal, so drug tests will not be an issue.

• Use could cause you to be mistaken for a steer and taken to the slaughterhouse.

About the Contributors

Tim Ziegenfuss, Ph.D., CSCS is the Chief Scientific Officer for an industry-leading, pharmaceutically-licensed nutritional supplement company. Tim is also an Adjunct Professor of Nutrition at Kent State University and has monthly columns in Physical Magazine and Muscular Development. Previously, "Dr. Z" spent five years as a college professor, teaching (Anatomy/Physiology, Sports Nutrition, Exercise Physiology) and researching sports supplements (creatine, protein, pyruvate, androstenedione, androstenediol, ma huang, ribose). You can contact Tim with questions about training, nutrition, or supplement use at: tzphd@hotmail.com

Stephen J. McGregor, Ph.D. received M.S. in molecular microbiology in 1995 from the University of Toledo, and a Ph.D. in Applied Physiology in 2001 from the University of Toledo. Dissertation work for the Ph.D. related to changes in gene expression resulting from contraction-induced muscle injury. Currently he’s an Assistant Professor of Exercise Science at Eastern Michigan University and co-director of the Nutriceutical Research and Training Institute.

© 1998 — 2002 Testosterone, LLC. All Rights Reserved.