Innovita Research Foundation

I.R.F. / Aging news / Cloning / 07111401

Super Mice after Gene Therapy
Posted on: November 14, 2007

Transgenic mice, containing a chimeric gene in which the cDNA for phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C) (EC [EC] 2) was linked to the α-skeletal actin gene promoter, express PEPCK-C in skeletal muscle (1-3 units/g). Breeding two founder lines together produced mice with an activity of PEPCK-C of 9 units/g of muscle (PEPCK-Cmus mice).

These mice were seven times more active in their cages than controls. On a mouse treadmill, PEPCK-Cmus mice ran up to 6 km at a speed of 20 m/min, whereas controls stopped at 0.2 km. PEPCK-Cmus mice had an enhanced exercise capacity, with a VO2max of 156 ± 8.0 ml/kg/min, a maximal respiratory exchange ratio of 0.91 ± 0.03, and a blood lactate concentration of 3.7 ± 1.0 mM after running for 32 min at a 25° grade; the values for control animals were 112 ± 21 ml/kg/min, 0.99 ± 0.08, and 8.1 ± 5.0 mM respectively.

The PEPCK-Cmus mice ate 60% more than controls but had half the body weight and 10% the body fat as determined by magnetic resonance imaging. In addition, the number of mitochondria and the content of triglyceride in the skeletal muscle of PEPCK-Cmus mice were greatly increased as compared with controls.

PEPCK-Cmus mice had an extended life span relative to control animals; mice up to an age of 2.5 years ran twice as fast as 6-12-month-old control animals. We conclude that overexpression of PEPCK-C repatterns energy metabolism and leads to greater longevity.

Source: Parvin Hakimi, Jianqi Yang, Gemma Casadesus, Duna Massillon, Fatima Tolentino-Silva, Colleen K. Nye, Marco E. Cabrera, David R. Hagen, Christopher B. Utter, Yacoub Baghdy, David H. Johnson, David L. Wilson, John P. Kirwan, Satish C. Kalhan, and Richard W. Hanson; Overexpression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle Repatterns Energy Metabolism in the Mouse; J. Biol. Chem., Vol. 282, Issue 45, 32844-32855, November 9, 2007
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