By David N. Leff

Science Editor

It might put more meat on the table and more muscle on wasted bodies.

That's the double putative promise of a newly announced gene that encodes a protein its discoverers have named myostatin.

Myostatin's muscle-building prowess works in the breach. That is, it releases the developmental brakes that stop an embryo from piling on more and more skeletal muscle mass once it's reached enough for its future body plan.

So when molecular biologist and geneticist Se-Jin Lee, at Johns Hopkins University, in Baltimore, raised a breed of knockout mice devoid of the myostatin gene, the newborn rodents grew into hulking brutes with huge hips and shoulders. Their total bodily skeletal muscle mass reached two to three times that of their normal litter mates.

Aside from their outsize murine physique, these myostatin-negative mice exhibited normal behavior and produced normal progeny.

Lee's group discovered the myostatin gene, initially labeled GDF-8, for growth/ differentiation factor. He is principal author of a paper in the May 1 issue of Nature. Its title: "Regulation of skeletal muscle mass in mice by a new TGF-ß superfamily member."

That genomic superfamily, to which myostatin (GDF-8) is the latest addition, numbers some 26 members to date — and still counting. These molecules hold down important jobs in regulating embryonic development and in assuring the well-being of tissues in adult animals, including humans.

Since submitting his report to Nature last November, Lee has advanced basic myostatin research along two tracks: human disease and livestock husbandry.

"What was not included in that manuscript," he told BioWorld Today, "was that we've since cloned the myostatin gene from many species. In terms of human therapeutics, we've got the human gene, and with respect to agriculture, the genes for cow, pig, sheep, chicken -- you name it."

He added: "We've purified the myostatin protein now and investigated its biological activity, such as receptor-binding, mostly in vitro. We haven't identified the GDF-8 receptor yet, but it's something we're actively pursuing.

"One of the things we're particularly keen on with respect to authenticating myostatin's function in humans," Lee continued, "is looking for naturally occurring human mutations that might correlate with differences in body build. But that work's just beginning."

In particular, "we're looking into the role the human GDF-8 gene may play in treating muscle-wasting disorders, such as muscular dystrophy and cachexia resulting from cancer or AIDS."

Myostatin's Conceivable Cancer Connection

But there's a good-sized caveat attached to that therapeutic outlook: myostatin's possible role as an oncogene.

"The basis for that concern," Lee explained, "is that several members of this superfamily are clearly involved in tumor-suppressing pathways. One clear-cut example is TGF-ß itself, for which mutations in the receptor or in the signaling pathway have been shown to lead to tumorigenesis, including colon and pancreatic cancer."

He cited another example, "inhibin-alpha, which is perhaps even more dramatic. Knockout mice lacking this factor develop gonadal tumors at an early age," Lee went on. "If you remove the gonads, the animal doesn't die of that cancer; it develops adrenal tumors instead."

So employing myostatin in clinical therapy still needs work. But Lee is optimistic: "We haven't seen any cancer yet in our myostatin-minus mice over the past full year of their two-year life expectancy," he observed.

On this score, he sees "probably no major concern in terms of agriculture. If tumors do develop, and everything is analogous to the muscular mice, the cancers would occur at such a late age that the animals most likely would be taken to market before that anyway."

Two years ago, Johns Hopkins and Genetics Institute Inc., of Cambridge, Mass., set up a joint venture, MetaMorphix Inc., to develop and commercialize drugs based on the transforming growth factor-beta molecules. (See BioWorld Today, May 2, 1995, p. 5.) Lee, its scientific founder, serves as a consultant to the company.

This week, its vice president and chief scientific officer, immunologist Larry Ellingsworth, moved into the firm's 6,000-square-foot premises, located in the Technical Center of the University of Maryland's Baltimore campus.

Ellingsworth told BioWorld Today that Genetics Institute has provided the start-up firm with "a major equity investment of $6 million total."

His first order of business is to revise MetaMorphix's original business plan, "because we see in myostatin an opportunity not only in human therapy but also in the area of agriculture."

Meat Now, Therapies Later

"The possibility we're talking about is creating new breeds of commercial livestock with more muscle mass and less fat content. This is very different, for example, from genetically engineering a growth-hormone transgenic animal. Growth hormone acts to increase the size of many different tissues, so you may end up with larger animals that get to market faster.

"But I think the promise of myostatin," he continued, "is that all of the excess body weight is in muscle -- or meat. There is no concomitant increase in fat. So essentially everything extra that the animal might eat, if it's really proportional to total body weight, might be 20 to 30 percent more. And all of that is going into meat."

On the subject of fat, myostatin is strikingly analogous to leptin, Lee pointed out, although the latter is not a member of the TGF-beta superfamily.

"The reason we drew the analogy," he explained, "is that leptin is a secreted factor; so is myostatin. Leptin is made specifically by fat, myostatin specifically by muscle. Loss of leptin function leads to an increase in fat, loss of myostatin function to an increase in muscle."

That's as far as the parallels go. There is no sequence homology between the two molecules. "Leptin is known to exert its effect by acting on the central nervous system to regulate complex behaviors related to metabolism and appetite control," Lee pointed out. "As for myostatin, we don't know. It may be acting locally, or it may be acting at a distant site in the body." *