New ‘mighty mice’ that run for 6 hours without stopping created

November 14th, 2007 - 8:15 am ICT by admin  
The study, led by Parvin Hakimi, a researcher in the Hanson lab, developed the new line of PEKCK-C mice over the past five years as part of on-going research, which was aimed at understanding the metabolic and physiological functioning of PEPCK-C in skeletal muscle and adipose tissue.

The transgenic mice, which have numbered nearly 500, were derived from six founder lines that contained 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.

In the study, the team 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.

The skeletal actin gene promoter directs expression of PEPCK-C exclusively to skeletal muscle.

The study found that 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.

Richard W. Hanson, the Leonard and Jean Skeggs Professor of Biochemistry at Case Western Reserve and the senior author of the study said that the new breed of mouse utilised fatty acids for producing the energy to do so much of physical activity.

“They are metabolically similar to Lance Armstrong biking up the Pyrenees; they utilize mainly fatty acids for energy and produce very little lactic acid,” Hanson said.

The study found that the genetically engineered mice ate 60 percent more than controls, but remained fitter, trimmer and lived and bred longer than wild mice in a control group.

Few female PEPCK-Cmus mice have had offspring at 2.5 years of age, which is an amazing feat considering that after mice are one year old they do not reproduce.

According to Hanson, the key to the extraordinary alteration in energy metabolism is the over-expression of the gene for the enzyme phosphoenolypyruvate carboxykinases (PEPCK-C).

The researchers stated 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, which dramatically raised the blood lactate levels.

The 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,” the researchers said.

“Understanding the biochemical mechanisms responsible for this repatterning of energy metabolism will keep us busy for some time to come,” they added.

Hakimi said that it was evident from the beginning that these mice were very different from average mice.

“From a very early age, the PEPCK-Cmus mice ran continuously in their cages,” she said.

Hakim said that she could identify which mice were from this new line by simply watching their level of activity in their home cage.

Animal behaviours studies later demonstrated that the PEPCK-Cmus mice were seven times more active in their home cages than controls; in addition, the mice were also markedly more aggressive.

The study is issued in the Journal of Biological Chemistry. (ANI)

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