Overexpression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse.
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 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 degrees 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.
Hakimi
Parvin
P
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4935, USA.
Yang
Jianqi
J
Casadesus
Gemma
G
Massillon
Duna
D
Tolentino-Silva
Fatima
F
Nye
Colleen K
CK
Cabrera
Marco E
ME
Hagen
David R
DR
Utter
Christopher B
CB
Baghdy
Yacoub
Y
Johnson
David H
DH
Wilson
David L
DL
Kirwan
John P
JP
Kalhan
Satish C
SC
Hanson
Richard W
RW
D000375:Aging / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal; D003600:Cytosol / Q000201:enzymology*; D004734:Energy Metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000201:enzymology*; D009928:Organ Specificity; D010375:Pedigree; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D012119:Respiration
D010729:Phosphoenolpyruvate Carboxykinase (GTP)
J Biol Chem. 2004 Nov 19;279(47):48941-9
15347677
Biochem J. 1967 May;103(2):391-9
4291786
Science. 2002 Apr 12;296(5566):349-52
11951046
Biochem Med Metab Biol. 1986 Jun;35(3):260-6
3521681
Diabetes. 2002 Mar;51(3):624-30
11872659
Ann N Y Acad Sci. 2004 Jun;1019:412-23
15247056
Biochem J. 1972 Jan;126(1):49-58
4342385
Biochem J. 1967 Sep;104(3):866-71
6049928
Am J Physiol. 1996 May;270(5 Pt 1):C1413-20
8967442
J Biol Chem. 2002 Aug 23;277(34):30409-12
12087111
Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10709-13
17548828
J Appl Physiol (1985). 1998 Jan;84(1):69-76
9451619
Nutr Metab (Lond). 2005 Nov 21;2:33
16300682
J Clin Invest. 2000 Oct;106(7):847-56
11018072
J Biol Chem. 1979 Jan 25;254(2):420-30
762069
J Biol Chem. 1988 Aug 15;263(23):11443-51
2841327
J Biol Chem. 1993 Jan 5;268(1):719-25
7678010
Am J Physiol. 1990 Dec;259(6 Pt 2):R1214-9
2175569
Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7111-6
12764228
Nature. 2000 Jul 27;406(6794):415-8
10935638
Biochem Biophys Res Commun. 2002 Aug 16;296(2):350-4
12163024
J Lipid Res. 1975 Mar;16(2):79-91
1168684
Cell. 1999 Jul 9;98(1):115-24
10412986
Eur J Appl Physiol Occup Physiol. 1986;55(3):330-3
3732261
J Biol Chem. 1981 Oct 25;256(20):10224-7
6169717
Science. 2000 Sep 22;289(5487):2126-8
11000115
J Biol Chem. 1957 May;226(1):497-509
13428781
FASEB J. 2005 May;19(7):786-8
15716393
Nature. 2002 Aug 15;418(6899):797-801
12181572
J Physiol. 1997 Aug 1;502 ( Pt 3):703-13
9279819
Biochem J. 1977 Feb 15;162(2):399-403
849291
J Biol Chem. 1990 Dec 25;265(36):22371-9
1702419
Biochem J. 1978 Nov 15;176(2):623-6
217368
J Biol Chem. 1976 Jan 10;251(1):37-44
1244353
J Biol Chem. 2003 Aug 15;278(33):30413-6
12788931
Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):625-30
11792850
Am J Physiol. 1990 Nov;259(5 Pt 1):C834-41
2240197
J Appl Physiol (1985). 2001 Mar;90(3):1137-57
11181630
J Gerontol. 1993 May;48(3):B97-100
8482812
Nature. 2005 Oct 20;437(7062):1109-11
16148943
J Physiol. 2006 Jul 1;574(Pt 1):33-9
16709637
Cell Metab. 2007 Jan;5(1):35-46
17189205
Equine Vet J Suppl. 2002 Sep;(34):275-8
12405700
J Histochem Cytochem. 1990 Feb;38(2):171-8
1688895
J Biol Chem. 2005 May 20;280(20):19587-93
15767263
J Appl Physiol (1985). 1992 Jun;72(6):2197-202
1629073
Am J Physiol Cell Physiol. 2000 Dec;279(6):C1870-9
11078702
Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14379-84
16980408
Eur J Biochem. 1980 Sep;110(2):371-7
7439166
PLoS Med. 2007 Mar;4(3):e76
17341128
PLoS Biol. 2004 Oct;2(10):e294
15328533