Myostatin. Heard of it?

Whether you have or not, myostatin is circulating inside your body at this very moment…and it’s got a growth-restraining order on your muscles.

The tiny myostatin protein conveys a powerful biological message to your muscle cells -and it’s not anything along the lines of “let’s get ready to grow”.

Quite the contrary, myostatin is proving to play a major role in your body’s resistance to bigger muscles, i.e., your failure to grow to the dimensions you truly desire. However, as this article will show, recent technological developments may make it possible for you to enjoy ‘hypertrophic freedom’ in the not-too-distant future. Planet Muscle, of course, will be the first to report on these industry-shaking developments.

Did you feel that? Another myostatin molecule just fit itself neatly into a receptor on the membrane of your muscle cell. Oops! There goes another one! Right now, many thousands of such myostatin-receptor interactions are triggering a flurry of biochemical events that will serve to keep your muscle cells from getting as big as you’d like.

“But I work out like a maniac! I eat 300 grams of protein a day!”, you protest. Which is all fine and good. Yet your gains in muscle size are unsatisfactory, are they not? Yes, and myostatin has a great deal to do with this.

choke collar
n.
A chain collar that tightens like a noose when the leash is pulled. Used to train or control dogs or other animals. Also called choke chain.

myostatin
n.
A protein, the product of the myostatin gene, that tightens like a noose on the protein-building machinery of muscle cells. Used to limit and restrict muscle growth in adults. Generally detested by bodybuilders. Also called the skinny protein.

Indeed, myostatin could well be regarded as Mother Nature’s ‘choke collar’ on muscle growth (Whittmore et al., 2003). Hence, the ‘skinny protein’. Myostatin powerfully suppresses the protein-building machinery of your muscle cells (more on this later), restricting them to only a very limited degree of growth. In this way, myostatin effectively keeps your muscles from getting bigger than is necessary to cope with the average situation reasonably well.

Okay, maybe not good enough for you and I, but certainly good enough for Mother Nature.

Yes, biological evolution -natural selection, if you like- favors not the magnificent, but the moderate. The human body got us to this point because it could cope with the average situation faced by our ancestors tens to hundreds of thousands of years ago reasonably well. This reasonable coping power is programmed into the supercoiled helices of your very own DNA - your genes. Genes, furthermore, which carry much the same messages that they carried in your prehistoric kin.

The trouble is that socially and culturally, things are anything but the same. Your modern-day wants frequently clash with what your biological needs were for the bulk of your evolutionary journey. In short, human biology hasn’t caught up with the times! Thus, bodybuilders like you and I have desires for muscular size (among others) that often far exceed what our genes are able to pony up.

Bodybuilding is about anything but moderation, or coping ‘reasonably well’. It is all about grandiosity, both in spirit (ego) and in physical dimensions. Just visit the lobby of the Mandelay Bay hotel on Mr. Olympia Weekend to see what I mean!

While myostatin may be helpless at keeping your ego on a leash, it does an exceptional job at negatively modulating, or restricting, the growth of your muscles. Only with years of exhaustive training and entire chicken farms of protein do your hair-like muscle cells show substantial increases in diameter. Even then, the gains can be annoyingly small --perhaps even unnoticeable to you and your all-too-critical peers.

Every day I pass by tiny shrubs, bushes and other caricatures of plant life as I walk down the street. I look at them and wonder: Do any of these plants harbor a myostatin ‘neutralizer’? Is nature hiding a substance with which to effectively break free of the choke collar on my muscle-building machinery?

Maybe. Maybe not. In any case, the search for a myostatin ‘neutralizer’ is certainly worthwhile. It is also well underway (see below).

Case in point: Studies on animals harboring mutations in the myostatin gene. These animals demonstrate dramatically enhanced muscle growth and an equally astonishing reduction in body fat -precisely what you and I are after.

Arnold et al. (2001) refer to myostatin ‘knockout’ mice (i.e., mice with a deleted myostatin gene) that display

“bulging muscular development visible all over their bodies, with the most extreme hypertrophy apparent in the shoulders and hindquarters…”

They go on to describe the so-called ‘double-muscled cattle’ that “are even more easily discernable than their murine [mouse] counterparts. On Belgian Blue bulls,

every intramuscular groove is readily visible, due to an almost complete lack of subcutaneous fat. Instead of the "boxy" build of typical cattle, double-muscled animals have tight, "greyhound" bellies…Indeed, they have a muscular conformation most often reserved for draft horses and bodybuilders - and such a blatant advertisement of retail product that the industry interest is obvious.”

Dr. Arnold’s group adds that the dramatic muscle growth seen in myostatin ‘null’ animals is specific to muscle tissue. Furthermore, the hypertrophy is observed throughout the body, and not merely specific to certain regions.

That’s an important question. Like the muscle tissue in some patients with growth-hormone secreting tumors, will the muscle created by myostatin inhibition be larger than normal, but weaker than expected?

Bogdanovich et al. (2002) provide some evidence to suggest that myostatin blockade will result in muscles that are as big as they are strong. When they injected mice with muscular dystrophy with an antibody to myostatin for three months, they found that:

“[the] increase in muscle strength was proportional to the degree of increase in muscle mass and offers physiological evidence for a functional improvement in [muscular dystrophic] muscle produced by myostatin blockade in vivo.”

Being a regulator of the growth and division of your muscle cells, you might expect the risk of side effects (e.g., cancer) upon ‘successfully’ blocking myostatin from doing its job.

Myostatin belongs to the transforming growth factor (TGF) family of growth factors. Like myostastin, transforming growth factor-beta (TGF-b) can act as a ‘choke collar’ on cell growth.

As one well-known (and technically articulate) industry expert remarked to me “Many substances have impact on TGF-b pathways but are hazardous as they can promote growth and survival of dysplastic and frankly malignant clonal populations.”

In other words, if you block myostatin, you may produce runaway cell division, also known as cancer.

The evidence to date, however, suggests that myostatin blockade will not produce cancer. Dr. Clifton Baile (2003), a Distinguished Professor of Animal Science and Foods and Nutrition at the University of Georgia, comments:

“Myostatin is also referred to as GDF-8, a subclass of at least 16 growth factors of the TGF gene family. The family of proteins as a composite has a plethora of actions. Some have activities [of those noted above] but not by GDF-8 or as the result of the inhibition of GDF-8.

There have been no increased incidence of tumors of any kind reported for any of the various types of mice produced where GDF-8 is inhibited or in any cattle breeds where no or mutated and inactive GDF-8 is produced. Specificity of the action of an inhibitor for GDF-8 may be important and one of the most difficult qualities to obtain.”

When your body makes, or synthesizes, more muscle protein than it breaks down over time, we generally expect bigger muscles to result.

There’s more to it than that. You may have already heard of satellite cells. For our purposes, you can think of them as ‘baby’, or immature, muscle cells. Satellite cells can divide to make copies of themselves. This is termed proliferation. They can also merge with your ‘adult’, or mature, muscle cells and donate their DNA in times of need.

In fact, the proliferation of your satellite cells is essential for muscle growth (Allen et al., 1979). [NOTE: Since satellite cell proliferation increases the total amount of DNA in a muscle (Oksbjerg et al., 2002), and the protein synthesis capacity is reflected in the RNA levels (Millward et al., 1973), we can measure these two things to get a feel for the anabolic state of a muscle cell.]

Ah, yes, the ones with algae in them.

Perhaps you’ve heard of glucosamine? The stuff for your joints?

Heparin is a carbohydrate (a.k.a. ‘polysaccharide’) that occurs all over your body, especially in the lining of your blood vessels and the spaces between your cells. (Many scientists believe that heparin is not active when taken orally. But in fact, Canadian researchers have determined that this isn’t entirely true.)

One of heparin’s building blocks is glucosamine. Heparin often occurs with sulfur attached to it, i.e., heparin sulfate. Thus, heparin sulfate may be referred to as a ‘sulfated polysaccharide’.

Many different growth-regulating proteins in your body, including myostatin, can bind to heparin. These heparin interactions may serve to ‘store’ the proteins until they are needed, concentrate them near their receptors (e.g., IGF-1 near the IGF-1 receptor) and/or protect them from inactivation by protein-digesting enzymes.

The sites on the protein that make heparin binding possible are called, appropriately enough, ‘heparin binding sites’. Heparin binding sites are very common in growth-regulating proteins, and have been used to purify myostatin.

So-called myostatin ‘inhibitors’ currently on the market contain a ‘sulfated polysaccharide’, analogous to heparin sulfate, from a ‘natural’, ‘exotic’ salt-water algae. The ads claim that this sulfated polysaccharide binds myostatin better than heparin. They go on to say that because the interest in this product was so extensive, they decided to dispense with any further studies and let the public buy this miraculous product immediately.

You be the judge. Does that sound like direct clinical proof of efficacy to you?

Of course, many substances in nature (possibly even inside your fridge) may well show strong myostatin binding activity. But until we do a double-blind clinical trial on humans and demonstrate the oral activity of such a substance ---most importantly, its ability to increase muscle mass and reduce fat mass-we’re just theorizing, at best.

One fact overlooked by marketers of existing ‘myostatin inhibitors’ is that myostatin seems to circulate in the blood as a latent, or inactive, complex (Whittmore et al., 2003). Even if you consumed enough of a ‘sulfated polysaccharide’ to transiently bind a biologically significant amount of myostatin, what would that do to its activity when it is already in a latent complex? I don’t know. Do you?

Questions remain, to be sure. And products that tout claims like “we were too bloody excited about this stuff to do any studies on it” do nothing but stall the answering of these questions.

Myostatin seems to put a choke collar on the activity of your satellite cells and the protein-building machinery of your mature muscle cells. Release this choke collar, therefore, and your anabolic devices will presumably be free to engage in muscle growth at a pace Mother Nature never intended.

“To date…myostatin is the only secreted protein that has been demonstrated to play a negative role in regulating muscle mass in vivo. Although additional experiments will be required to prove aspects of this overall model and to identify the other signaling components, our data suggest that myostatin antagonists, such as follistatin and the myostatin propeptide, or activin type II receptor antagonists may be effective muscle-enhancing agents for both human and agricultural applications.” (Lee and McPherron, 2001).

To use the phraseology of Drs. Lee and McPherron, ‘antagonizing’ myostatin is precisely what one University-based company is planning on doing. This group of anabolically-oriented scientists (let’s call them ‘Newco’) is developing a number of in vitro (cell-based) assays with which to screen for natural, orally bioavailable products with myostatin-‘neutralizing’ activity. In vivo (whole animal) assays -ultimately involving human beings-will be developed to confirm the findings of the in vitro work.

In other words, and uniquely, the product(s) discovered by Newco will hit the shelf neatly dressed in direct clinical proof of efficacy ---proven to do something of compelling important to you (i.e., building muscle, removing fat).

• Increases in muscle mass with proportional increases in muscle strength (big muscles that are as strong as they look)
• Reductions in body fat (get much leaner)
• Increases in caloric output (eat more without getting fat)

All too frequently, bodybuilding, weight-loss and other dietary supplements come to you, the consumer, naked of any direct scientific support. This not only cheats you; it also cheats and undermines the industry as a whole.

To repeat, any products touting claims for myostatin ‘neutralization’, ‘inhibition’, or the like must be accompanied by direct clinical proof of efficacy. This means confirmation of myostatin inhibition by in vitro work, followed by confirmation of safety and body composition enhancement in animal models and, ultimately, human clinical trials.

Furthermore, we want specific inhibition of myostatin. We don’t want to ‘neutralize’ any other cell proliferation/differentiation regulating substances. That could lead to illness. As Dr. Baile explains, specific inhibition of myostatin may be the most difficult thing to screen for. But it’s possible.

The potential applications of Newco’s technologies are tremendous: obesity, type II diabetes, muscular dystrophies and other conditions of muscle wasting (e.g., cancer, AIDs, space travel), and of course, bodybuilding and general weight-management.

Will there soon be safe, orally active, natural products capable of inhibiting myostatin and freeing your muscles to grow as you desire?

Don’t miss an issue of Planet Muscle, and you’ll be assured of finding out!