More than a century ago, livestock breeders in Europe observed that some of their cattle were more muscled than others.
THE MYOSTATIN GENE
Super Cows and Mighty Mice by Elzi Volk

In 1997, scientists McPherron and Lee revealed to the public the "secret" of an anomaly that livestock breeders have capitalized since the 1800's: the gene responsible for big beefy cows (1). More than a century ago, livestock breeders in Europe observed that some of their cattle were more muscled than others. Being dabblers in genetics, they selectively bred these cattle to increase the progeny displaying this trait. Thus two breeds of cattle (Belgian Blue and Piedmontese) were developed that typically exhibit an increase in muscle mass relative to other conventional cattle breeds. Little did they know that many years later Mighty Mouse would be more than merely a cartoon.

A team of scientists led by McPherron and Lee at John Hopkins University was investigating a group of proteins that regulate cell growth and differentiation. During their investigations they discovered the gene that may be responsible for the phenomenon of increased muscle mass, also called "double-muscling" (1,2). Myostatin, the protein that the gene encodes, is a member of a super-family of related molecules called transforming growth factors beta (TGF-b). It is also referred to as growth and differentiation factor-8 (GDF-8). By knocking out the gene for mysotatin in mice, they were able to show that the transgenic mice developed two to three times more muscle than mice that contained the same gene intact. Lee commented that the myostatin gene knockout mice "look like Schwarzenegger mice." (3).

Further exploration of genes present in skeletal muscle in the two breeds of double-muscled cattle revealed mutations in the gene that codes for myostatin. The double-muscling trait of the myostatin gene knockout mice and the double-muscled cattle demonstrates that myostatin performs the same biological function in these two species. Apparently, myostatin may inhibit the growth of skeletal muscle. Knocking out the gene in transgenic mice or mutations in the gene such as in the double-muscled cattle result in larger muscle mass. This discovery has paved the way for a plethora of futuristic implications from breeding super-muscled livestock to treatment of human muscle wasting diseases.

Researchers are developing methods to interfere with expression and function of myostatin and its gene to produce commercial livestock that have more muscle mass and less fat content. Myostatin inhibitors may be developed to treat muscle wasting in human disorders such as muscular dystrophy. However, several public media sources immediately raised the issue of abusing myostatin inhibitors by athletes. In addition, a hypothesis has been put forth that a genetic propensity for high levels of myostatin is responsible for the lack of muscle gain in weight trainees. Accordingly, this article presents a look at the science of myostatin and its implications for the athletic arena.

What is Myostatin? - Growth Factors...

Before we can understand the implications of tampering with mysotatin and its gene, we must learn what myostatin is and what it does. Higher organisms are comprised of many different types of cells whose growth, development and function must be coordinated for the function of individual tissues and the entire organism. This is attainable by specific intercellular signals, which control tissue growth, development and function. These molecular signals elicit a cascade of events in the target cells, referred to as cell signaling, leading to an ultimate response in or by the cell.

Classical hormones are long-range signaling molecules (called endocrine). These substances are produced and secreted by cells or tissues and circulated through the blood supply and other bodily fluids to influence the activity of cells or tissues elsewhere in the body. However, growth factors are typically synthesized by cells and affect cellular function of the same cell (autocrine) or another cell nearby (paracrine). These molecules are the determinants of cell differentiation, growth, mobility, gene expression, and how a group of cells function as a tissue or organ.

Growth factors (GF) are normally effective in very low concentrations and have high affinity for their corresponding receptors on target cells. For each type of GF there is a spcific receptor in the cell membrane or nucleus. When bound to their ligand, the receptor-ligan complex initiates an intracellular signal inside of the cell (or nucleus) and modifies the cell's function.

A GF may have different biological effects depending on the type of cell with which it interacts. The response of a target cell depends greatly on the receptors that cell expresses. Some GFs, such as Insulin-like growth factor-I, have broad specificity and and affect many classes of cells. Others act only on one cell type and elicit a specific response.

Many growth factors promote or inhibit cellular function and may be multifactoral. In other words, two or more substances may be required to induce a specific cellular response. Proliferation, growth and development of most cells require a specific combination of GFs rather than a single GF. Growth promoting substances may be counterbalanced by growth inhibiting substances (and vice versa) much like a feedback system. The point where many of these substances coincide to produce a specific response depends on other regulatory factors, such as environmental or otherwise.

Transforming Growth Factors

Some GFs stimulate cell proliferation and others inhibit it, while others may stimulate at one concentration and inhibit at another. Based on their biological function, GFs are a large set of proteins. They are usually grouped together on the basis of amino acid sequence and tertiary structure. A large group of GFs is the transforming growth factor beta (TGFb) superfamily of which there are several subtypes. They exert multiple effects on cell function and are extensively expressed.

A common feature of TGFb's is that they are secreted by cells in an inactive complex form. Consequently, they have little or no biological activity until the latent complex is broken down. The exact mechanism(s) involved in activating these latent complexes is not completely understood, but it may involve specific enzymes. This further exemplifies how growth factors are involved in a complex system of interaction.