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Research Highlight - Born to Run

“ We gotta get out while we’re still young, Cause tramps like us baby, we were born to run.”
Bruce Springsteen: Born to run

Researchers in Dr. Richard Hanson's Laboratory have bred a line of “mighty mice” (PEPCK-Cmus mice) that run much faster for a much longer time than normal mice. These genetically engineered mice 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 capacity is an alteration in energy metabolism that results from over-expression of the gene for the enzyme phosphoenolpyruvate carboxykinase (PEPCK-C). “The mice are metabolically similar to Lance Armstrong biking up the Pyrenees; they utilize mainly fatty acids for energy and produce very little lactic acid,” Dr. Hanson says.

Parvin Hakimi, a researcher in the Hanson lab, developed this new line of PEKCK-C mice over 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 contain a chimeric gene where a copy of the cDNA for PEPCK-C was linked to the skeletal actin gene promoter. This promoter directs expression of PEPCK-C exclusively to skeletal muscle. 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 comments; “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. The mice were also 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 say.

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. 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 say. “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.” 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 raises blood lactate levels. This new mouse line also had an increased content of mitochondria and high concentrations of triglycerides in their skeletal muscles, which also contribute 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 says. “Understanding the biochemical mechanisms responsible for this repatterning of energy metabolism will keep us busy for some time to come.”

“The technique used to create the animal model reported in our study is not appropriate for application to humans. The ethical implications are such that this approach should not be used in humans, or is it technically possible at this time to efficiently introduce genes into human skeletal muscle, in order to mimic the effect seen in our mice” says Hanson. “Any attempt to tamper with the metabolic processes in human muscle will surely do more harm than good. We believe that this mouse model will provide important insights into the impact of prolonged exercise on the development of cancer in the animal, the effect of diet and exercise on longevity and will increase our knowledge of the factors that regulate energy metabolism in skeletal muscle.”

The work was described in 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.”

The PEPCK-C enzyme research has a long history at the Biochemistry Department. It was discovered in 1955 at the medical school by Merton F. Utter, a former chair of the department of biochemistry.

Adapted from a Case News Report.