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J. Biol. Chem., Vol. 283, Issue 7, 4228-4240, February 15, 2008

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Modest PGC-1 Overexpression in Muscle in Vivo Is Sufficient to Increase Insulin Sensitivity and Palmitate Oxidation in Subsarcolemmal, Not Intermyofibrillar, Mitochondria^*

Carley R. Benton¹, James G. Nickerson, James Lally, Xiao-Xia Han, Graham P. Holloway², Jan F. C. Glatz^¶3, Joost J. F. P. Luiken^¶4, Terry E. Graham, John J. Heikkila^||5, and Arend Bonen⁶

From the Departments of Kinesiology and ^||Biology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada, the ^¶Department of Molecular Genetics, Maastricht University, 6200 MD Maastricht, The Netherlands, and the Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada

PGC-1 overexpression in skeletal muscle, in vivo, has yielded disappointing and unexpected effects, including disrupted cellular integrity and insulin resistance. These unanticipated results may stem from an excessive PGC-1 overexpression in transgenic animals. Therefore, we examined the effects of a modest PGC-1 overexpression in a single rat muscle, in vivo, on fuel-handling proteins and insulin sensitivity. We also examined whether modest PGC-1 overexpression selectively targeted subsarcolemmal (SS) mitochondrial proteins and fatty acid oxidation, because SS mitochondria are metabolically more plastic than intermyofibrillar (IMF) mitochondria. Among metabolically heterogeneous rat hindlimb muscles, PGC-1 was highly correlated with their oxidative fiber content and with substrate transport proteins (GLUT4, FABPpm, and FAT/CD36) and mitochondrial proteins (COXIV and mTFA) but not with insulin-signaling proteins (phosphatidylinositol 3-kinase, IRS-1, and Akt2), nor with 5'-AMP-activated protein kinase, 2 subunit, and HSL. Transfection of PGC-1 into the red (RTA) and white tibialis anterior (WTA) compartments of the tibialis anterior muscle increased PGC-1 protein by 23-25%. This also induced the up-regulation of transport proteins (FAT/CD36, 35-195%; GLUT4, 20-32%) and 5'-AMP-activated protein kinase, 2 subunit (37-48%), but not other proteins (FABPpm, IRS-1, phosphatidylinositol 3-kinase, Akt2, and HSL). SS and IMF mitochondrial proteins were also up-regulated, including COXIV (15-75%), FAT/CD36 (17-30%), and mTFA (15-85%). PGC-1 overexpression also increased palmitate oxidation in SS (RTA, +116%; WTA, +40%) but not in IMF mitochondria, and increased insulin-stimulated phosphorylation of AKT2 (28-43%) and rates of glucose transport (RTA, +20%; WTA, +38%). Thus, in skeletal muscle in vivo, a modest PGC-1 overexpression up-regulated selected plasmalemmal and mitochondrial fuel-handling proteins, increased SS (not IMF) mitochondrial fatty acid oxidation, and improved insulin sensitivity.

Received for publication, May 25, 2007 , and in revised form, November 27, 2007.

^* This work was supported in part by grants from the Canadian Institutes of Health Research (to A. B. and T. G.), the Natural Sciences and Engineering Research Council of Canada (to A. B. and J. J. H.), the Netherlands Organization for Health Research and Development NWO-ZonMw Grant 40-00812-98-03075 (to J. L. and J. G.), the European Commission Integrated Project LSHM-CT-2004-005272, Exgenesis (to J. L. and J. G.), and the Canada Research Chair program (to J. J. H. and A. B.). 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.

¹ Supported by an Ontario graduate scholarship.

² Supported by an NSERC doctoral scholarship.

³ Netherlands Heart Foundation Professor of Cardiac Metabolism.

⁴ Recipient of a VIDI-Innovational Research Grant from the Netherlands Organization of Scientific Research NWO-ZonMw Grant 016.036.305.

⁵ Canada Research Chair in Stress Protein Gene Research.

⁶ Canada Research Chair in Metabolism and Health. To whom correspondence should be addressed. Tel.: 519-824-4120 (Ext. 53028); Fax: 519-763-5902; E-mail: abonen{at}uoguelph.ca.

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