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Overexpression 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 1

From the Departments of Biochemistry, ¶Nutrition, **Pediatrics, Neuroscience, and ||Biomedical Engineering, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4935 and the Department of Gastroenterology/Hepatology and Pathobiology, Cleveland Clinic Foundation, Cleveland, Ohio 44195

Transgenic mice, containing a chimeric gene in which the cDNA for phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C) (EC 4.1.1.3 [EC] 2) was linked to the -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.

Received for publication, July 25, 2007, and in revised form, August 21, 2007.

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