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uperSupplemental Material can be found at: THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 282, NO. 45, pp. 32844 –32855, November 9, 2007 © 2007 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A.

Overexpression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle RepatternsEnergy Metabolism in the Mouse*□

Received for publication, July 25, 2007, and in revised form, August 21, 2007 Published, JBC Papers in Press, August 23, 2007, DOI 10.1074/jbc.M706127200

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
Transgenicmice, containing a chimeric gene in which the cDNA for phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C) (EC 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 thancontrols. 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 tocontrol 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.

PEPCK-C2 is involved in gluconeogenesis in the liver and kidney cortex and in glyceroneogenesis in liver and white and

* This work was supported by National Institutes of Health GrantsDK058620

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, TheBiomedical 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. This article was selected as a Paper of the Week. □ S The on-line version of this article (availableat contains a video with sound showing mice performing a treadmill test. 1 To whom correspondence should be addressed. Tel.: 216-368-3880; Fax: 216-368-4544; E-mail: 2 The abbreviations used are: PEPCK-C, the cytosolic form of phosphoenolpyruvate carboxykinase (GTP); bGH, bovine growth hormone; PPAR, per-

brown adipose tissue (see Ref. 1 for a review)....
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