Of Mice and Men...and Muscle (part 3)

Read my previous posts on myostatin here and here.

Meet the whippets (click for larger version):

Whippets are a breed of dog developed specifically for racing. They were officially recognized as a breed in the late 1800s and can reportedly run up to 35 mph.

Take another look at the photos of whippets above. See anything interesting? If you look close, you might notice that the dogs get bigger from left to right. The heavily muscled dogs in the right column are referred to as ‘bully’ whippets by breeders. Apparently, whippet breeders brought this trait to the attention of the National Human Genome Research Institute at NIH. Knowing about the role of myostatin mutations in producing other examples of double muscling, the researchers went looking for mutations in the myostatin gene of whippets.

The results are pretty nicely summed up by the pictures. Wild type whippets (lacking any mutation in the myostatin gene) are on the far left, heterozygotes (dogs that possess one copy of a normal myostatin gene and one copy with a mutation that produces a malfunctioning protein) in the middle, and individuals (bullies) with two copies of the mutation on the right.

If that was the end of the story, it would be interesting to scientists (and useful to dog breeders), but not much else. What makes this more newsworthy is that the researchers were able to connect the genetics with athletic performance.

I don’t know anything about dog racing, but racing whippets are apparently divided into four classes: A, B, C, D. Think of it like the system used in professional baseball in the US (or like soccer leagues in the rest of the world). The fastest dogs are A, the slowest in D. It turns out that dogs with the mutation make up a disproportionate number of dogs in the faster classes. We now have a quantitative connection between genes and performance. (I should point out that the faster dogs almost always possess only one copy of the mutation, not two. I don’t think dogs with two copies of the mutation generally are raced. Muscle bound perhaps?)

This brings me back to the boy in Germany who also has two mutated copies of the myostatin gene. His mother, who was a professional athlete and comes from a family with several members noted for their strength, has one copy of the mutation.

Given that high level athletes have shown themselves willing to do lots of things to gain an advantage over the competition, and knowing that drugs are in the pipeline that would inhibit myostatin, how long will it be before athletes are trying to build muscle by blocking their myostatin? Or how long before the national Olympic training programs or college scouts start screening for these mutations to guarantee that funds for training are spent on athletes with the best genes?

As the authors of the whippet research note:

“Our findings have implications for competitive and professional sports. Here, we show that a disruption in the function of the MSTN [myostatin] gene increases an individual’s overall athletic performance in a robust and measurable way. …

The potential to increase an athlete’s performance by disrupting MSTN either by natural or perhaps artificial means could change the face of competitive human and canine athletics. Given the poorly understood consequences for overall health and well-being, caution should be exercised when acting upon these results.”

References:

1. Mosher, D.S. et al. (2007). "A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs." PLoS Genetics 3(5): e79 (doi:10.1371/journal.pgen.0030079)

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 dy^W/dy^W) 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 clinicaltrials.gov, 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…

References:

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.