Impaired expression of NADH dehydrogenase subunit 1 and PPARgamma coactivator-1 in skeletal muscle of ZDF rats: restoration by troglitazone.
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-alpha (PPARalpha) 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 pyruvate dehydrogenase 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 PPARgamma 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.
Jové
Mireia
M
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Spain.
Salla
Joel
J
Planavila
Anna
A
Cabrero
Agatha
A
Michalik
Liliane
L
Wahli
Walter
W
Laguna
Juan C
JC
Vázquez-Carrera
Manuel
M
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D004272:DNA, Mitochondrial / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D007473:Ion Channels; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000077288:Troglitazone; D000071246:Uncoupling Protein 2
D001786:Blood Glucose; D002839:Chromans; D004272:DNA, Mitochondrial; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D000071246:Uncoupling Protein 2; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D009245:NADH Dehydrogenase; C490791:mt-Nd1 protein, rat; D000077288:Troglitazone