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Review
. 2008 Jun;90(6):838-42.
doi: 10.1016/j.biochi.2008.03.009. Epub 2008 Apr 3.

Born to Run; The Story of the PEPCK-Cmus Mouse

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Free PMC article
Review

Born to Run; The Story of the PEPCK-Cmus Mouse

Richard W Hanson et al. Biochimie. .
Free PMC article

Abstract

In order to study the role of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK-C) in skeletal muscle, PEPCK-Cmus mice were created by introducing the cDNA for the enzyme, linked to the human alpha-skeletal actin gene promoter, into their germ line. Two founder lines generated by this procedure were bred together, creating a line of mice that have 9.0 units/g skeletal muscle of PEPCK-C, as compared to 0.080 units/g in muscle from control animals. The mice were more active than controls in their cages and could run for up to 5 km, at a speed of 20 m/min without stopping (control mice run for 0.2 km at the same speed). Male PEPCK-Cmus mice are extremely aggressive, as well as hyperactive. During strenuous exercise, they use fatty acids as a fuel more efficiently than do controls and produce far less lactate than do control animals, perhaps due to the greatly increased number of mitochondria in their skeletal muscle. PEPCK-Cmus mice also store up to five-times more triglyceride in their skeletal muscle, but have only marginal amounts of triglyceride in their adipose tissue depots, despite eating 60% more than controls. The concentration of leptin and insulin the blood of 8-12 months of PEPCK-Cmus mice is far lower than noted in the blood of control animals of the same age. These mice live longer than controls and the females remain reproductively active for as long as 35 months. The possible reasons for the profound alteration in activity and longevity caused the introduction of a simple metabolic enzyme into the skeletal muscle of the mice will be discussed.

Figures

Figure 1
Figure 1. Possible mechanism to explain the phenotype of the PEPCK-Cmus mice
The over-expression of PEPCK-C in skeletal muscle leads to a greatly enhanced rate of glyceroneogenesis in the tissue and the accumulation of triglyceride. This results in increased fatty acid oxidation in the tissue and the subsequent stimulation of mitochondrial biogenesis. The increased mitochondria, and the availability of ample fatty acids as a fuel in the muscle, are responsible for the hyperactivity noted in the PEPCK-Cmus mice. The hyperactivity results in a marked reduction adipose tissue mass in the animals, which results in a lower level of leptin secretion, increasing food intake in the mice. The hyperactivity increases the insulin sensitivity of the muscle, recruiting GLUT-4 to the cell surface in the absence of insulin. The result is a lowered concentration of insulin over the life span of the mice. The reason for the prolongation of reproductive capacity in female PEPCK-Cmus mice is not clear. Finally, an understanding of the cause of the behavioral changes noted with the PEPCK-Cmus mice will require investigation
Figure 2
Figure 2. The metabolism on glutamine in the kidney: the role of anaplerosis and cataplerosis in citric acid cycle flux
The conversion of glutamine to glucose in the kidney cortex illustrates the metabolic role of PEPCK-C as a cataplerotic enzyme (see text for details)

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