Transgenic mice, containing a chimeric gene in which the cDNA for phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C) (EC 220.127.116.11 [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.