The child was also abnormally muscular. His quadriceps had twice the cross-sectional area as that of children of a comparable age and sex. His subcutaneous fat was half as thick.
In 1997, only three years before the child’s birth, researchers at the Johns Hopkins University School of Medicine had discovered a gene that, when expression of the gene was blocked, caused abnormally large muscle growth in mice. Mice lacking a functioning copy of the gene had muscles 2-3 times the mass of mice that did have a functioning copy. The gene, initially called GDF-8, belongs to the TGF-β gene family. (GDF stands for growth and differentiation factor; TGF is short for transforming growth factor.) The members of this family of genes regulate growth and differentiation. Because the normal function of GDF-8 was to limit muscle growth, the researchers named it myostatin (myo for muscle, statin because it seemed to inhibit muscle growth).
In their own words:
“GDF-8 null animals are significantly larger than wild-type animals and show a large and widespread increase in skeletal muscle mass. Individual muscles of mutant animals weigh 2-3 times more than those of wild-type animals, and the increase in mass appears to result from a combination of muscle cell hyperplasia and hypertrophy. These results suggest that GDF-8 functions specifically as a negative regulator of skeletal muscle growth.”
[In the photo, taken from McPherron et al (1997), normal (wild-type) mouse on top, mouse without myostatin on bottom.]
This discovery was perhaps a bit more than just another brick in the wall of molecular biology and gene function. As the scientists noted, manipulation of either the gene, its expression, or its signaling pathway in cells had potential implications for treatment of diseases like muscular dystrophy or the muscle wasting that occurs in patients immobilized for long periods or those suffering from cancer (cancer cachexia). However, they also commented that it might have agricultural implications (think chicken breast and beef cattle).
In fact, within months, of the discovery of myostatin, several research groups had sequenced the gene in cattle and identified the mutations that produced two breeds noted for their extraordinary muscle: Belgian blues and Piedmontese. In these cattle, the phenomenon was known as “double muscling.” In both breeds, mutations in the myostatin gene prevented the animals from produce enough (or any) functioning protein from the myostatin gene. As a result, the negative regulation of muscle growth was lacking and muscle was more massive. The meat of these breeds is reported to be more tender than other meat because it apparently has less connective tissue. On the downside, calves generally have to be delivered by C-section because they are so large at birth.
But the research on myostatin hasn't been all about agriculture. It also has been an active subject of research related to Duchenne muscular dystrophy. I’ll discuss some of that research soon.
- Schuelke, M. et al. (2004). "Myostatin mutation associated with gross muscle hypertrophy in a child." New England Journal of Medicine (June 24) 350: 2682-8. (I think it's available free with registration?)
- McPherron, A.C. et al. (1997). "Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member." Nature (May 1) 387: 83-90. (subcription required)
- McPherron, A.C. and SJ Lee (1997). "Double muscling in cattle due to mutations in the myostatin gene." Proc. Nat'l Acad. Sci. (USA) 94: 12457-61.