Supermouse

 
This CNN report tells us about a supermouse created by Hansen's group at Case Western Reserve University (Hakimi et al. 2007). They inserted an extra copy of the PEPCK gene into the mouse genome and drove expression of that gene in muscle cells. The mice with extra PEPCK in their muscle cells were seven times more active than normal mice. As you can see in the CNN report, they can run on a treadmill for much longer times than mice without the extra PEPCK.



I'm sure most of know about Phosphoenolpyruvate carboxykinase (PEPCK) because it's a really important enzyme. For the very few who don't know their biochemistry pathways, here's a brief lesson.

Here's a simplified overview of the main biosynthesis pathways. The important ones are gluconeogenesis (the biosynthesis of glucose) and the citric acid cycle. Various intermediates in the citric acid cycle are used for synthesis of amino acids. One of them, oxaloacetate, is the substrate for PEPCK in a reaction that converts oxaloacetate to phosphoenolpyruvate.

This is a way to use the carbon atoms of citric acid cycle intermediates in the synthesis of glucose. Under normal circumstances the intermediates in the citric acid cycle don't change very much but their concentration can increase when amino acids are degraded in the reverse of the amino acid synthesis pathways shown here.

The activity of the supermouse is explained by increases in the number of mitochondria in muscle cells and more efficient utilization of oxygen. It is not clear why an increase in PEPCK levels causes such a drastic effect. It could be due to the fact that the mammalian version of PEPCK uses GTP ...


and one of the reactions in the citric acid cycle requires GDP. This could increase flux in the citric acid cycle leading to greater synthesis of ATP in the mitochondrial membranes. (The greater the flux, the more NADH is produced, and every mole of NADH makes 2.5 moles of ATP.)

Alternatively, the increase in stamina could be due to the fact that oxaloacetate is removed from the pool of citric acid cycle intermediates and this results in increased flux since the pools don't become too large when amino acid are broken down to citric acid cycle intermediates.

Finally, increased PEPCK activity could produce more phosphoenolpyruvate which is readily converted to acetyl CoA that can be used in the synthesis of triglycerides (fatty acids) [THEME: Pyruvate Dehydrogenase]. The storage of fatty acids supplies an energy-rich source that can be used up during exercise. In normal mice, the energy is derived from glucose molecules stored as glycogen but fatty acids are better.

All these possibilities are discussed in the paper but no definite conclusions are reached. Richard Hansen has been working on this enzyme for thirty years and it's truly remarkable that we still don't have a good idea about its role in mammalian metabolism. PEPCK is found in all species and it seems clear in most species that it plays a role in the biosynthesis of glucose from fatty acids. In species other than mammals, the citric acid cycle is short-circuited by the glyoxylate pathway which provides a route for acetyl CoA to be converted to glucose. Acetyl CoA is produced when fatty acids are degraded. Mammals don't have the glyoxylate pathway enzymes.

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Hakimi, P., Yang, J., Casadesus, G., Massillon, D., Tolentino-Silva, F., Nye, C.K., Cabrera, M.E., Hagen, D.R., Utter, C.B., Baghdy, Y., Johnson, D.H., Wilson, D.L., Kirwan, J.P., Kalhan, S.C. and Hanson, R.W. (2007) Overexpression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle Repatterns Energy Metabolism in the Mouse. J Biol Chem. 282:32844-32855. [PubMed]