Monday, 9 April 2012

PEPCK-C Super Mice

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The thought of a little mouse performing the equivalent of running up and down mountains for half a day if they were humans is overwhelming. How is this possible? Well, with genetic modification advancement this is very possible. Take a selection of standard mice, tweak their genetic code a little, complete several generations of selective breeding and amazingly, you too could have a pocket super mouse. Case Western Reserve University School of Medicine and Cleveland Clinic Foundation have undertaken this task to create super mice, and in 2007, “Overexpression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle Repatterns Energy Metabolism in the Mouse” was released (Hakimi, et al, 2007).

Average mice have been genetically modified by Hakimi, aiming to understand the overexpression of the enzyme Phosphoenolpyruvate Carboxykinase in skeletal muscle and its effects (Appleyard, 2007). Phosphoenolpyruvate Carboxykinase is also referred to as PEPCK-C, which in unmodified animals is found in the liver. PEPCK-C is an enzyme used in the process of gluconeogenesis, part of metabolic functions in animals (Holyoak, 2006). In the study, six family lines of genetically modified mice were used. A segment of the alpha-skeletal actin gene was linked to the 1976-bc cDNA and finalised by the 3’ end of the bGH gene, allowing excess production of PEPCK-C enzyme within the mice (Hakimi, et al, 2007). Two family lines were most suitable for breeding the highest activity of PEPCK-C enzyme, after nine generations of crossbreeding, the perfect line of high PEPCK-C mice was created. This line produced approximately 9 units/g of PEPCK-C, as opposed to 1-3 units/g of PEPCK-C in control mice (Cool, 2007). The excess PEPCK-C allowed the mice to use fatty acids as an energy source during physical activity, whereas control mice use glycogen as the main source (Chen, 2007).

Within their cages it was revealed that PEPCK-C mice were aggressive and continuously active, compared to controls. It was believed the mice could suffer from mental illnesses or disorders, but this was unapparent. Increased physical activity was measured by distance travelled, rearing frequency and velocity of the PEPCK-C mice compared to the controls. The greatest test for the mice was treadmill testing. Control mice were able to run up to 0.2km at 20m/min, where PEPCK-C mice were able to run up to 6km at 20m/min, a 30x increase (Hakimi, et al, 2007).

PEPCK-C mice had less weight and body fat, even after eating 60% more. Similar aged control mice had 2-3 times more body fat than genetically modified mice. The increase in metabolism was associated with a higher number of mitochondria in cells (Appleyard, 2007). Confirmed by electron microscopy (Hakimi, et al, 2007).

PEPCK-C has shown that with genetic modification many unnatural things are possible. This could lead to the advancement of drugs for humans, to improve health. Hanson (cited in Cool, 2007) believes the study method is unsuitable to be applied to humans, the ethical implications considered too great. This opens a whole new world into the advancement of genetics, which could affect humans in the future.

Video of PEPCK-C mice compared to controls – Treadmill Experiment: http://www.jbc.org/content/suppl/2007/10/30/M706127200.DC1/Supermouse_Video_-_Official_(Windows).wmv

Reference List


Appleyard, B, 2007, ‘Mighty Mouse – he’ll make champions of us all’, Supercentenarian.com, viewed 20/3/2012, < http://www.supercentenarian.com/archive/pepck-c.html>.

Chen, G 2007, ‘Liver lipid molecules induce PEPCK-C gene transcription and attenuate insulin action’, Biochemical and Biophysical Research Communications, vol. 361, pp. 805-810

Cool, H 2007, ‘Case Western Reserve Researchers Breed a Mighty Mouse’, Case Western Reserve University, viewed 18/03/2012, < http://blog.case.edu/case-news/2007/11/02/mightymouse>.

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’, The Journal of Biological Chemistry, vol. 282, No. 45, pp. 32844-32855, DOI 10.1074/jbc.M706127200.

Holyoak, T, Sullivan, S.M, Nowak, T, 2006, ‘Structural Insights into the Mechanism of PEPCK Catalysis’, Biochemistry, vol. 45, pp. 8254-8263

McGraw-Hill Concise Dictionary of Modern Medicine, 2002, ‘Stereotypy’, viewed 19/03/2012, http://medical-dictionary.thefreedictionary.com/stereotypy

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