Wednesday, July 4, 2007

Of Mice and Men...and Muscle (part 2)

For part 1 of my post on myostatin, go here.

From the beginning, it was apparent to researchers that myostatin might provide treatment options for musculodegenerative diseases like muscular dystrophy. In 2002, researchers showed that by blocking activity of the protein produced by the myostatin gene with an antibody, mice from a strain used as a mouse model of Duchenne muscular dystrophy (known as mdx mice) had greater body weight, muscle mass, and muscle strength than mdx mice that did not receive the antibody. The same research group repeated the research in a study published in 2005 using a different method to block myostatin and got similar results.

[Note on figure: EDL = extensor digitorum longus. In humans, this muscle is located in your shin and is one of several muscles that acts in dorsiflexion of foot. (To do this, stand with your feet flat on ground and raise the ball of your foot off the floor.)]

Unfortunately, research on other strains of mice wasn’t so positive. Using a strain of mice (referred to as dyW/dyW) that acts as a model of a different kind of muscular dystrophy, researchers in southern California found that, although the mice without myostatin had more muscle, they suffered from the same clinical problems that the control mice did. Even worse, it appeared that a decrease in fat due to the lack of myostatin (lack of myostatin makes muscles bigger with less fat) caused increased mortality in the mice. So, not only did blocking myostatin not help, it actually made things worse.

A year later, another research group (this time from Ohio and Chicago) examined the effects of blocking myostatin in a third strain of mice. This strain, known as scgd -/-, lacks a molecule called δ-sarcoglycan, a protein that sticks out from the cell membrane and forms part of a complex of molecules that helps stabilize the cell membrane of muscle cells. In humans, a similar defect produces limb-girdle muscular dystrophy, a very rare type of MD.

The outcome of this research emphasized the variability in blocking myostatin. Using mice that had received an antibody blocking myostatin beginning at 4 weeks old and other mice that began receiving the antibody at 20 weeks old, the researchers found that the younger mice received greater benefits than did the older mice. Also, reaction to the treatment varied depending on the particular muscle group under consideration. For example, the quadriceps (thigh muscle) was larger in the 20 week old mice that received the antibody blocking myostatin, but the gastrocnemius (calf muscle) was smaller than untreated mice.

Finally, to cloud the water even more, a recent study published in the Proceedings of the National Academy of Sciences indicated that bigger muscles may not mean stronger muscles. This study simply blocked the myostatin gene in otherwise normal mice, then tested the force of contraction of the muscles. It turns out that the force of contraction was not significantly different between mice without myostatin and control mice. And, since the muscles of the mice lacking myostatin were bigger, the force per unit mass of muscle was actually less than the force of contraction in control mice.

This research throws a cloud over the research described above that found mice with blocked myostatin had muscles that contracted with greater force than mice without blocked myostatin. The main difference between the two studies is the mice: normal mice without myostatin in the PNAS study, and mdx mice without myostatin in the other.

The upshot of all of this is that the effect of blocking myostatin seems to depend on age of the intervention, the strain of mice receiving the intervention, and the particular muscle under consideration.

Despite all this, pharmaceutical companies have completed clinical trials in humans (phase I/II). According to, Wyeth has completed phase I and II on stamulumab (MYO-029). The MDA website notes that the data are currently being analyzed.

We’ll have to wait and see if inhibiting myostatin turns out to be a workable treatment for any types of MD. But there’s one other aspect of myostatin’s usefulness that I haven’t really touched on. It will bring us back to the baby with mutations in his genes for myostatin. Stay tuned, sports fans…


  1. Bogdanovich, S. et al. (2002). "Functional improvement of dystrophic muscle by myostatin blockade." Nature 420: 418-421. (Nov. 28)
  2. Bogdanovich, S. et al. (2005). "Myostatin propeptide-mediated amelioration of dystrophic pathophysiology." FASEB J 19: 543-549.
  3. Li, Z. et al. (2005). "Elimination of myostatin does not combat muscular dystrophy in dy mice but increases postnatal lethality." American Journal of Pathology 166(2): 491-497.
  4. Parsons, S.A. et al. (2006). "Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdlemuscular dystrophy."American Journal of Pathology 168(6): 1975-1985.
  5. Amthor, H. et al. (2007). "Lack of myostatin results in excessive muscle growth but impaired force generation." PNAS 104(6): 1835-1840 (Feb. 6)
See links to abstracts of papers in text of post.

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