The transcriptional coactivators, PGC-1α and β, cooperate to maintain cardiac mitochondrial function during the early stages of insulin resistance

Abstract 

We previously demonstrated a cardiac mitochondrial biogenic response in insulin resistant mice that requires the nuclear receptor transcription factor PPARα. We hypothesized that the PPARα coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is necessary for mitochondrial biogenesis in insulin resistant hearts and that this response was adaptive. Mitochondrial phenotype was assessed in insulin resistant mouse models in wild-type (WT) versus PGC-1α deficient (PGC-1α^−/−) backgrounds. Both high fat-fed (HFD) WT and 6week-old Ob/Ob animals exhibited a significant increase in myocardial mitochondrial volume density compared to standard chow fed or WT controls. In contrast, HFD PGC-1α^−/− and Ob/Ob-PGC-1α^−/− hearts lacked a mitochondrial biogenic response. PGC-1α gene expression was increased in 6week-old Ob/Ob animals, followed by a decline in 8week-old Ob/Ob animals with more severe glucose intolerance. Mitochondrial respiratory function was increased in 6week-old Ob/Ob animals, but not in Ob/Ob-PGC-1α^−/− mice and not in 8week-old Ob/Ob animals, suggesting a loss of the early adaptive response, consistent with the loss of PGC-1α upregulation. Animals that were deficient for PGC-1α and heterozygous for the related coactivator PGC-1β (PGC-1α^−/−β^+/−) were bred to the Ob/Ob mice. Ob/Ob-PGC-1α^−/−β^+/− hearts exhibited dramatically reduced mitochondrial respiratory capacity. Finally, the mitochondrial biogenic response was triggered in H9C2 myotubes by exposure to oleate, an effect that was blunted with shRNA-mediated PGC-1 “knockdown”. We conclude that PGC-1 signaling is important for the adaptive cardiac mitochondrial biogenic response that occurs during the early stages of insulin resistance. This response occurs in a cell autonomous manner and likely involves exposure to high levels of free fatty acids.

Abbreviations: PPAR, peroxisome proliferator-activated receptor, ERR, estrogen related receptor, PGC-1, PPAR gamma coactivator-1, FAO, fatty acid oxidation, FA, fatty acid, WT, wild-type, HF, high fat, NORC, Nutrition Oriented Research Center, WUSM, Washington University School of Medicine, AUC, area under the curve, TAG, triacylglyceride, GTT, glucose tolerance test, EM, electron microscopy, LV, left ventricle, OXPHOS, oxidative phosphorylation, PC, palmitoyl-L-carnitine, ECHO, echocardiogram, IVCT, interventricular contraction time, KD, knockdown, OCR, oxygen consumption rate

Keywords: Diabetes, Insulin resistance, Cardiomyopathy, Mitochondria, Heart failure, Metabolism