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Journal of Lipid Research, Vol. 45, 113-123, January 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Impaired expression of NADH dehydrogenase subunit 1 and PPAR coactivator-1 in skeletal muscle of ZDF rats

Mireia Jové^*, Joel Salla^*, Anna Planavila^*, Àgatha Cabrero^*, Liliane Michalik, Walter Wahli, Juan C. Laguna^* and Manuel Vázquez-Carrera^1,*

^* Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Spain
Institut de Biologie Animale, University of Lausanne, Switzerland

¹ To whom correspondence should be addressed. e-mail: mvazquezcarrera{at}ub.edu

Type 2 diabetes has been related to a decrease of mitochondrial DNA (mtDNA) content. In this study, we show increased expression of the peroxisome proliferator-activated receptor- (PPAR) and its target genes involved in fatty acid metabolism in skeletal muscle of Zucker Diabetic Fatty (ZDF) (fa/fa) rats. In contrast, the mRNA levels of genes involved in glucose transport and utilization (GLUT4 and phosphofructokinase) were decreased, whereas the expression of pyruvatedehydrogenase kinase 4 (PDK-4), which suppresses glucose oxidation, was increased. The shift from glucose to fatty acids as the source of energy in skeletal muscle of ZDF rats was accompanied by a reduction of subunit 1 of complex I (NADH dehydrogenase subunit 1, ND1) and subunit II of complex IV (cytochrome c oxidase II, COII), two genes of the electronic transport chain encoded by mtDNA. The transcript levels of PPAR Coactivator 1 (PGC-1) showed a significant reduction. Treatment with troglitazone (30 mg/kg/day) for 15 days reduced insulin values and reversed the increase in PDK-4 mRNA levels, suggesting improved insulin sensitivity. In addition, troglitazone treatment restored ND1 and PGC-1 expression in skeletal muscle.

These results suggest that troglitazone may avoid mitochondrial metabolic derangement during the development of diabetes mellitus 2 in skeletal muscle.

Abbreviations: ACO, acyl-CoA oxidase; COII, complex IV, cytochrome c oxidase subunit II; CPT-I, carnitine palmitoyltransferase I; CTE, cytosolic acyl-CoA thioesterase; mtDNA, mitochondrial DNA; mtTFA, mitochondrial transcription factor A; ND1, subunit 1 of complex I; NRF-1, nuclear respiratory factor-1; PDK-4, pyruvate dehydrogenase kinase 4; PFK, phosphofructokinase; PGC-1, PPAR coactivator 1; PPAR, peroxisome proliferator-activated receptor; UCP-2, uncoupling protein 2; ZDF, Zucker diabetic fatty

Supplementary key words subunit 1 of complex I • peroxisome proliferator-activated- coactivator 1 • subunit II of complex IV • electronic transport chain • Zucker diabetic fatty • peroxisome proliferator-activated receptor • uncoupling protein • dehydrogenase subunit 1 • reduced nicotinamide adenine dinucleotide

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