Researchers breed a mighty mouse

Nov 01, 2007

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 Richard W. Hanson, the Leonard and Jean 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.”

Source: Case Western Reserve University

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drivin98
not rated yet Nov 01, 2007
I think I saw this movie. >_
earls
not rated yet Nov 02, 2007
Is there any other way to curb lactic acid production besides gene therapy? What kind of steroids was Lance on?
KB6
4 / 5 (1) Nov 02, 2007
We may be looking at the beginning of the next "steroids." It depends on whether or not they can eventually make some sort of useful drug from this research, which then, like steroids, will leak into athletics. As the technologies of human self-transformation continue to progress, athletics, especially professional athletics, will be one of the first things to become obsolete. It's already being subverted.
earls
not rated yet Nov 02, 2007
Yes, agreed. There is a major problem looming on the horizon in reference to athletics. Just look at that kid with no legs that was discriminated against by the Olympic committee. I'm not saying I don't understand where they're coming from, attempting to maintain the "purity" of the games, but how far are they going to take it?

To the extreme, imagine someone with a shot putt cannon arm... Obviously, a regular person isn't going to be able to compete against something like that. Ok, so you invent a new competition for everyone with shot putt cannon arms. But every cannon arm is different, how do you go about putting a cap on technology?

It's kind of like the problem NASCAR is facing. You could build a car faster than the rest with superior technologies... But you're not going to be able to compete unless you comply to the restricter plates and any other field leveling technology. There's already cheating and people pushing the limits... It's going to become a nightmare to try and enforce any kinds of standards.
MrGrynch
not rated yet Nov 02, 2007
Aside from the performance enhancements, lets not forget the fact that these mice seemed to live longer with a greater quality of life, as measured by their activity level for their age. This could have a profound impact on the elderly allowing us to live more active lives for more years.
Rushon
not rated yet Nov 02, 2007
This is obveous racism - it is a WHITE mouse. u dont see any black mice in those pictures do you? they are only giving superior genes to white mice because they think white is a superior color.

This is just the first step in a plot to give white people genes to compeet with the black man in sports and other dominance bcause they can't handle it. I can't belive you are all snowed by this by thinking this is just about mice only when it is a cover story. hello, white reserchers, white mice, white people? this is completely racist and you should all work with me to get these guys fired from their jobs.