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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« A Less-Than-Subtle Plan | Main | Colors May Fade »

April 15, 2002

A Treadmill Pill?

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Posted by Derek

There was quite a wave of publicity about a possible "exercise pill" recently. The folks over at Godless Capitalist asked me to take a crack at explaining what all the noise is about. As you might imagine, though, the original research that set this off is a bit less sensational: "Regulation of Mitochondrial Biogenesis in Skeletal Muscle by CaMK" is the catchy title, from a joint effort of teams at Duke and Southwestern/Dallas.

For a long time, it's been known that the key to a muscle's capacity is the number of mitochondria in its cells. Those, of course, are the organelle responsible for energy production. The more you have, the longer you can go without fatigue (which is really just a buildup of toxic waste products formed when the mitochondria can't keep up with demand, and the cell has to switch to other, less efficient pathways.)

It's also been known for decades that exercise causes more mitochondria to be produced inside muscle cells (along with plenty of other changes,) but the genes that are turned on and off to do that are still pretty obscure. One of the things that happens with exercise is elevated calcium levels in the cells, which sets off the activity of several enzymes. These researchers engineered a form of one particular enzyme, CaMK-IV, so that it would be activated even without raised calcium levels. They also took out the section of the protein that would normally keep it inactive under baseline conditions, so the enzyme was set to be set to full activity the entire time.

The transgenic mice made with this mutation are interesting animals. Their pattern of gene expression (and the corresponding levels of various proteins) make their muscles look very similar to normal muscle after extended physical training. Thus the "exercise pill" hype - the mice seem to have developed with pre-exercised muscle tissue.

And, sure enough, microscopic examination showed that the mutant mice had about 50% more mitrochondria in their muscle cells. The teams also identified raised amounts of a protein (PGC-1) that's known to be very important in metabolic balance in fat and muscle tissue. The best guess is that the engineered activity of the CaMK-IV enzyme set off production of more PGC-1, which led to more mitochondria. No one had made that enzyme-PGC connection before - it'll be useful to know that, because PGC-1 has key roles to play in obesity and diabetes, as well as in exercise.

So, now we have a better idea of how muscles figure out how to respond to exercise. Do we have an exercise pill? Nowhere near. Keep in mind that these mice had to be genetically altered to get the activated enzyme. Getting that effect with a drug won't be easy.

One problem is that it's more or less impossible to get an enzyme to do what it does better or more quickly. They're built for speed already. What you can do is find some other system that's naturally slowing it down, and try to gum that pathway up instead, freeing the enzyme of interest to do its thing. (A general motif of medicinal chemistry is that we're a lot better at throwing wrenches into the works than we are at tuning them up to work better; millions of years of evolution are hard to outdo.) There's no guarantee that we'd be able to do this trick with CaMK-IV.

And if we did, there's no telling what might happen (although I'm sure that someone's going to give it a try, and more power to them.) Genetically altered mice, who've had their entire embryonic development to deal with some mutation, can behave very differently from normal adult mice that get suddenly thrown into the same state. A number of these gain-of-function enzyme experiments, for example, have yielded results that don't seem to apply well to the real world (although this one, admittedly, makes a lot of sense.) Don't cash in the health club membership just yet.

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