Over-expression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse

doi:10.1074/jbc.M706127200

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Papers In Press, published online ahead of print August 23, 2007
J. Biol. Chem, 10.1074/jbc.M706127200
Submitted on July 25, 2007
Revised on August 21, 2007
Accepted on August 23, 2007

Over-expression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse

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

Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4935

Corresponding Author: rwh{at}case.edu

Transgenic mice, containing a chimeric gene in which the cDNA for phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C) (EC 4.1.1.32) was linked to the $alpha$ -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 muscle (PEPCK-C^mus mice). These mice were seven times more active in their cages than controls. On a mouse treadmill, PEPCK-C^mus mice ran up to 6 km at a speed of 20 m/min while controls stopped at 0.2 km. PEPCK-C^mus mice had an enhanced running ability, with a VO₂ max of 156 ± 8.0 ml/kg/min, a maximal Respiratory Exchange Ratio (RER) of 0.91 ± 0.03 and a blood lactate concentration of 3.7 ± 1.0 mM after running for 32 min at a 25º 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-C^mus mice eat 60% more than controls, but had half the body weight and 10% the body fat as determined by MRI. In addition, the number of mitochondria and the content of triglyceride in the skeletal muscle of PEPCK-C^mus mice was greatly increased as compared to controls. PEPCK-C^mus 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 over-expression of PEPCK-C repatterns energy metabolism and leads to greater longevity.

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