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First published online October 17, 2008
Journal of Experimental Biology 211, iii (2008)
Copyright © 2008 The Company of Biologists Limited
doi: 10.1242/jeb.024265

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Outside JEB

DRUG COCKTAIL COULD SUBSTITUTE FOR EXERCISE

Glenn Lurman

University of Bern

glenn.lurman{at}ana.unibe.ch

Most of us have seen the infomercials in the wee hours selling us fitness in various forms. You need only take a certain pill for a couple of weeks and you will become as strong as Superman. It now appears that may soon be more than just a late-night claim. In a multi-centre study led by Ronald Evans from the Salk Institute, the pharmacological action of two drugs and how they are able to mimic the effects of exercise on mouse skeletal muscle have been revealed.

Within mammalian muscle tissue there are essentially two types of muscle cells. Type I are slow contracting, generate energy through oxidative metabolism and are responsible for the endurance typical of long distance running. Type II muscle cells on the other hand are fast contracting and rely on anaerobic glycolysis to produce energy. As such they are responsible for rapid, powerful movements, for example during jumping or weight lifting. Different training regimes and types of exercise will cause shifts in the relative proportions of these two types of muscle cells. Evans and his colleagues wanted to explore the cellular signalling pathways responsible for such shifts.

Starting several years ago, the team developed transgenic mice that over-express a cell signalling molecule (PPAR) that is critical for the regulation of skeletal muscle metabolism. These mice exhibited increased oxidative metabolic enzymes and a shift in the fibre type, with muscles having proportionally more type I oxidative muscle cells than type II. The end result was an increase in the endurance of the transgenic mice of 60–75%, but this enhanced endurance was only seen in combination with exercise training, indicating that a second stimulus was necessary to enhance the development of type I muscle.

To better understand the mechanism of the training stimulus, Evans and his team compared gene expression profiles of trained non-transgenic mice, mice treated with a PPAR stimulant and mice that received doses of the PPAR stimulant along with a training regime. Although many of the gene expression patterns overlapped, each condition had a distinct expression signature. Consequently, Evans suggested that the pharmacological activation of a second critical signalling pathway (AMPK), which is known to be stimulated by exercise, might act as a substitute for exercise.

The team then gave non-transgenic mice two pharmacological agents that stimulated each of the two (i.e. PPAR and AMPK) pathways. They found that the combined action of the two drugs led to an increase in expression of genes involved in oxidative metabolism and blood vessel growth and an associated reduction in the levels of enzymes involved in glycolytic metabolism. This was combined with a shift in the muscle fibre types from glycolytic type II fibres to oxidative type I fibres. And when the team tested the animals they found that pharmacological activation of these two cellular pathways led to a significant increase in their endurance.

The potential applications of such pharmacological agents have not escaped the attention of clinicians and these drugs offer huge potential in the treatment of a number of diseases. On the other hand, this may well prove to be yet another headache for sport's World Anti-Doping Agency with secretive supermen competing alongside orthodox athletes.

References

Narkar, V. A., Downes, M., Yu, R. T., Embler, E., Wang, Y.-X., Banayo, E., Mihaylova, M. M., Nelson, M. C., Zou, Y., Juguilon, H., Kang, H., Shaw, R. J. and Evans, R. M. (2008). AMPK and PPAR agonists are exercise mimetics. Cell 134,405 -415.[Medline]

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lurman, G. Search for Related Content PubMed Articles by Lurman, G. Social Bookmarking                         What's this?