| First Author | Mitra R | Year | 2012 |
| Journal | J Mol Cell Cardiol | Volume | 52 |
| Issue | 3 | Pages | 701-10 |
| PubMed ID | 22080103 | Mgi Jnum | J:183668 |
| Mgi Id | MGI:5319059 | Doi | 10.1016/j.yjmcc.2011.10.010 |
| Citation | Mitra R, et al. (2012) The transcriptional coactivators, PGC-1alpha and beta, cooperate to maintain cardiac mitochondrial function during the early stages of insulin resistance. J Mol Cell Cardiol 52(3):701-10 |
| abstractText | We previously demonstrated a cardiac mitochondrial biogenic response in insulin resistant mice that requires the nuclear receptor transcription factor PPARalpha. We hypothesized that the PPARalpha coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha) 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-1alpha deficient (PGC-1alpha(-/-)) backgrounds. Both high fat-fed (HFD) WT and 6 week-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-1alpha(-/-) and Ob/Ob-PGC-1alpha(-/-) hearts lacked a mitochondrial biogenic response. PGC-1alpha gene expression was increased in 6 week-old Ob/Ob animals, followed by a decline in 8 week-old Ob/Ob animals with more severe glucose intolerance. Mitochondrial respiratory function was increased in 6 week-old Ob/Ob animals, but not in Ob/Ob-PGC-1alpha(-/-) mice and not in 8 week-old Ob/Ob animals, suggesting a loss of the early adaptive response, consistent with the loss of PGC-1alpha upregulation. Animals that were deficient for PGC-1alpha and heterozygous for the related coactivator PGC-1beta (PGC-1alpha(-/-)beta(+/-)) were bred to the Ob/Ob mice. Ob/Ob-PGC-1alpha(-/-)beta(+/-) 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. |
