NEW YORK (Reuters Health) - In the June 24th issue of The New England Journal of Medicine, clinicians describe a child with a loss-of-function mutation in the myostatin gene that led to gross muscle hypertrophy. This case, they say, provides “strong evidence” that this myostatin plays an important role in regulating muscle mass in humans, as it does in mice and cattle.
It also suggests that targeted therapeutic inactivation or inhibition of myostatin “might be a way to treat muscle wasting disorders such as Duchenne’s muscular dystrophy or muscle wasting due to prolonged inactivity such as in intensive care patients or in the elderly,” Dr. Markus Schuelke from Charite University Medical Center in Berlin told Reuters Health.
Myostatin, a member of the transforming growth factor beta family, regulates muscle mass during embryonal development as well as after birth. Myostatin knockout mice develop muscles that are twice the size of muscles in normal mice. “The patient described in the NEJM article shows that myostatin indeed has the same effect in humans,” Dr. Schuelke said.
At birth, clinicians noticed that the child had unusually large and well-defined muscles. He was later found to have a homozygous g-to-a transition at nucleotide g.IVS1+5 in a noncoding region of his myostatin gene. “The mutation was confirmed by restriction analysis and was absent in 200 alleles from control subjects with a similar ethnic background, thus excluding a common polymorphism,” the authors point out.
The child’s 24-year-old mother, a former professional athlete, is a heterozygous carrier of the same mutation. Several family members have also been reported to be “unusually strong,” although genetic analyses have not been performed on them.
So far, the child, now 4 years of age, has not experienced any health problems, although he continues to have enlarged muscle mass and is unusually strong for his age. “We are especially concerned about the long-term effects that inactivation of myostatin may have on his heart muscle since he may develop hypertrophy of the heart muscle,” Dr. Schuelke said.
The finding that myostatin is a negative regulator of muscle mass in humans and that its inactivation leads to increased muscle mass and strength has a number of potential clinical implications. Of note, experiments in the mdx mouse model of Duchenne’s muscular dystrophy have shown that injection of anti-myostatin antibodies may slow the disease progression.
“However, so far we do not know what the effect of long-term treatment with anti-myostatin antibodies will be,” Dr. Schuelke emphasized. “Careful long-term animal studies and observation of humans with myostatin mutations over a long period of time have to be done before these substances may safely enter a clinical trial,” he added.
In an editorial, Dr. Elizabeth M. McNally of the University of Chicago warns, “the potential for abuse outside of the medical arena is substantial.” She agrees that “further studies of the safety, efficacy, and long-term consequences of manipulating muscle growth are needed.”
Source: N Engl J Med 2004;350:2642-2644,2682-2688. [ Google search on this article ]
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