Re: swartznegger mice or super mice

Matt-

The super-mice or Schwarzenegger-mice were first reported back in the late 1990’s and was extensively covered by the press across the world. This particular group from the University of Pennsylvania used a technique that involved injecting a virus directly into muscle. The virus carried the gene for insulin-growth-factor-1 (IGF-1). This direct gene therapy resulted in about 25% increased strength in the affected muscles in this mouse model. As you can likely appreciate, there are many ethical and safety questions that need to be thoroughly investigated before these therapies (and others of this type) could/can be considered for humans, not the least of which is long-term side effects of both the intended treatment and the virus that is used to carry it.

More recently, other “mighty mice” have been developed that involve the gene for a protein called myostatin. It turns out that in cattle, mice, and even humans when both copies of the gene are inactive, a very lean and muscular development occurs due to more and larger muscle fibers. Also these mice seem to have increased ability to regenerate muscle tissue, although it is not clear if these mice are stronger. Interestingly, in 2004, a case involving a boy born in Germany was reported in the New England Journal of Medicine where a natural mutation resulted in both copies of the boy’s myostatin gene being inactive. The boy is extremely muscular and strong with muscle size and strength double that of children his age. This gene has been, and continues to be, well studied so that interactions with other genes and proteins can be better understood and also potentially develop treatment opportunities. In mice with some varieties of muscular dystrophy, blocking myostatin helped overcome the muscle degeneration associated with the disease. It is hoped that this approach will lead to treatments of muscular dystrophies as well as other diseases such as ALS. At least one major pharmaceutical company (Wyeth) has been trying to develop an antibody-based treatment that could be used to block the pathway that produces myostatin. Once again, the primary unknown factor for this therapy and similar therapies is long-term biological effects and safety.

Very recently a study appeared in the American Journal of Pathology (June 2006) that apparently shows in a mouse model of limb-girdle muscular dystrophy that loss of myostatin in early disease stage mice improved muscle mass and function but in late-stage mice did not seem to improve the condition. As with most studies, this recent piece to a very complicated puzzle yields wonderful information and data and yet is difficult to interpret for a number of scientific reasons. As is discussed in an accompanying commentary in the journal, “the key new finding of the study is that myostatin blockade is highly variable in its effectiveness” from muscle group to muscle group. This adds to the variability seen in other studies on mice where blocking myostatin seems to help muscle growth and strength for some kinds of muscular dystrophy and either not help or make conditions worse in another.

I hope this answer gives you some insight into the progress (and complications) around this line of research and why it can seem like progression toward a treatment is encouragingly very quick and agonizingly slow simultaneously. I was interested to see on a summary page that I found on WebMD ( http://www.emedicine.com/NEURO/topic189.htm) that for the many sub-types of limb-girdle dystrophy, most have an identified gene that is involved with its development or progression.

Keith Anderson
Brigham & Women's Hospital, Boston, MA, USA