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J. Biol. Chem., Vol. 282, Issue 45, 32844-32855, November 9, 2007

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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. Hanson¹

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-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, whereas controls stopped at 0.2 km. PEPCK-C^mus mice had an enhanced exercise capacity, with a VO_2max 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-C^mus 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-C^mus mice were greatly increased as compared with 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 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.

^* This work was supported by National Institutes of Health Grants DK058620 and DK025541 (to R. W. H.), GM-66309 (to M. E. C.), AG12834 (to J. P. K.), EB004070 (to D. L. W.), and CA43703 (to the Case Western Reserve University Comprehensive Cancer Center), by a Provost Vision Fund grant to support the Case Western Reserve University School of Medicine Behavioral Core Laboratory (to G. C.), by Grant NNJ06HD81G (to M. E. C.) from the NASA, and by an Ohio BRTT, The Biomedical Structure, Functional and Molecular Imaging Enterprise grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a video with sound showing mice performing a treadmill test.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed. Tel.: 216-368-3880; Fax: 216-368-4544; E-mail: rwh{at}case.edu.

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