Breeding Mighty Mice At Case Western Reserve

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Breeding Mighty Mice At Case Western Reserve

http://www.medicalnewstoday.com/articles/87528.php

Case Western Reserve University researchers have bred a line

of " mighty mice " (PEPCK-Cmus mice) that have the capability of

running five to six kilometers at a speed of 20 meters per minute on

a treadmill for up to six hours before stopping.

" They are metabolically similar to Lance Armstrong biking up the

Pyrenees; they utilize mainly fatty acids for energy and produce

very little lactic acid, " said W. Hanson, the Leonard and

Skeggs Professor of Biochemistry at Case Western Reserve and

the senior author of the cover article that appeared in the Journal

of Biological Chemistry, entitled " Over Expression of the Cytosolic

Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle

Repatterns Energy Metabolism in the Mouse. "

These genetically engineered mice also eat 60 percent more than

controls, but remain fitter, trimmer and live and breed longer than

wild mice in a control group. Some female PEPCK-Cmus mice have had

offspring at 2.5 years of age, an amazing feat considering most mice

do not reproduce after they are one year old. According to Hanson,

the key to this remarkable alteration in energy metabolism is the

over-expression of the gene for the enzyme phosphoenolypyruvate

carboxykinases (PEPCK-C).

Parvin Hakimi, the article's lead author and a researcher in the

Hanson lab, developed this new line of PEKCK-C mice over the past

five years as part of on-going research aimed at understanding the

metabolic and physiological function of PEPCK-C in skeletal muscle

and adipose tissue.

The transgenic mice, which now number nearly 500, were derived from

six founder lines that contain a chimeric gene in which a copy of

the cDNA for PEPCK-C was linked to the skeletal actin gene promoter,

containing the 3'-end of the bovine growth hormone gene. The

skeletal actin gene promoter directs expression of PEPCK-C

exclusively to skeletal muscle. Various lines of PEPCK-Cmus mice

expressed PEPCK-C at different levels, but one very active line of

PEPCK-Cmus mice had levels of PEPCK-C activity of 9 units/gram

skeletal muscle, compared to only 0.08 units/gram in the muscles of

control animals.

It was evident from the beginning that these mice were very

different from average mice. Hakimi commented, " From a very early

age, the PEPCK-Cmus mice ran continuously in their cages. " She said

she could identify which mice were from this new line by simply

watching their level of activity in their home cage. Animal behavior

studies later demonstrated that the PEPCK-Cmus mice are seven times

more active in their home cages than controls; in addition, the mice

were also markedly more aggressive. " The enhanced level of activity

noted in the PEPCK-Cmus mice extends well beyond two years of age;

this is considered old-age for mice, " the researchers said.

As part of this study, the researchers determined oxygen

consumption, the production of carbon dioxide and changes in the

lactate concentrations in the blood of the PEPCK-Cmus mice and

controls during strenuous exercises on a treadmill, which was set at

a 25-degree incline. The treadmill speed was increased by 2m/min

every minute until the mice stopped running. The PEPCK-Cmus mice ran

an average of 31.9 minutes, compared to 19 minutes for the control

animals.

" What is particularly dramatic is the difference in the

concentrations of lactate in the blood, " the researchers said. " At

the beginning of exercise, the concentration of lactate was similar

in two groups of mice, but by the end of the exercise period, the

control group had elevated levels of blood lactate with little

change in the levels in the PEPCK-Cmus mice. "

They added that this indicates that the PEPCK-Cmus mice relied

heavily on fatty acids as a source of energy during exercise, while

the control animals rapidly switched from fatty acid metabolism to

using muscle glycogen (carbohydrates) as a fuel; this dramatically

raised the blood lactate levels.

This new mouse line also has an increased content of mitochondria

and high concentrations of triglycerides in their skeletal muscles,

which also contributed to the increased metabolic rate and longevity

of the animals.

" It is remarkable that the over-expression of a single enzyme

involved in a metabolic pathway should result in such a profound

alteration in the phenotype of the mouse, " Hakimi and Hanson

said. " Understanding the biochemical mechanisms responsible for this

repatterning of energy metabolism will keep us busy for some time to

come. "