Friday, November 02, 2007

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 [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.

For details see the article by Hakimi et al., pages 32844–32855.


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