Friday, November 2, 2007

Researchers at Case Western University in Cleveland, Ohio have announced the creation of transgenic mice with substantially improved athletic endurance, which live and breed longer and are more aggressive than genetically unmodified siblings, and are leaner despite consuming 60% more food. The mice have been dubbed “mighty mice” or “supermice” by the popular press and have been compared to cyclist Lance Armstrong.

The changes were created by adding an extra copy of a single gene, PEPCK-C. This gene is already present in the mouse genome, but the modified gene is designed to be strongly active (transcribed) in skeletal muscle. (The natural copy of the gene, most active in the liver, continues to function normally). The gene mediates a crucial rate controlling step of gluconeogenesis and glyceroneogenesis, and its activity helps to allow energy production by the mitochondrial citric acid cycle. In the transgenics, more energy is available to muscle through the burning of fatty acids, with much less production of lactate (a chemical that leads to sore muscles when one exercises). This is not as major a change to the mouse genome as it might seem to the layperson. The PEPCK-C gene is already present in the mouse and a variety of natural mutations could likely cause similar results. The study appears today in the Journal of Biological Chemistry in a paper with lead author Parvin Hakimi from the laboratory of Richard W. Hanson.

The altered mice can run at 20 meters per minute (0.75 miles per hour or 1.2 kilometers per hour) for up to six kilometers (nearly four miles) without stopping. The average treadmill time for strenuous exercise on a 25-degree incline is 31.9 minutes, well in excess of the 19 minute average of unmodified mice. Females can breed at two and a half years of age, whereas most female mice cannot breed after the first year.

A colony of 500 mice has been bred, starting from six independent germline transformations (“founder” mice). The level of PEPCK-C in muscle is 9 units per gram of muscle as opposed to only 0.08 in normal mice. Levels of triglycerides and the number of mitochondria are also increased.

Hanson said that he did not expect that the results would be applicable to humans due to both practical and ethical considerations in addition to the fact that the genes might not function the same way in humans.

This is not the first time that the press has dubbed a genetically modified mouse a “mighty mouse”. Earlier scientists at John Hopkins University announced that they had made mice with massively increased muscle mass that were larger and stronger than their normal cousins. These alterations increased strength rather than endurance through the genetic modification of myostatin and follistatin, or by injection of a soluble form of ACVR2B to block myostatin activity in normal mice.