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The transcriptional coactivators, PGC-1α and β, cooperate to maintain cardiac mitochondrial function during the early stages of insulin resistance.
J Mol Cell Cardiol. 2012 Mar; 52(3):701-10.JM

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 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-1α(-/-) and Ob/Ob-PGC-1α(-/-) hearts lacked a mitochondrial biogenic response. PGC-1α 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-1α(-/-) mice and not in 8 week-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.

Authors+Show Affiliations

Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22080103

Citation

Mitra, Riddhi, et al. "The Transcriptional Coactivators, PGC-1α and Β, Cooperate to Maintain Cardiac Mitochondrial Function During the Early Stages of Insulin Resistance." Journal of Molecular and Cellular Cardiology, vol. 52, no. 3, 2012, pp. 701-10.
Mitra R, Nogee DP, Zechner JF, et al. The transcriptional coactivators, PGC-1α and β, cooperate to maintain cardiac mitochondrial function during the early stages of insulin resistance. J Mol Cell Cardiol. 2012;52(3):701-10.
Mitra, R., Nogee, D. P., Zechner, J. F., Yea, K., Gierasch, C. M., Kovacs, A., Medeiros, D. M., Kelly, D. P., & Duncan, J. G. (2012). The transcriptional coactivators, PGC-1α and β, cooperate to maintain cardiac mitochondrial function during the early stages of insulin resistance. Journal of Molecular and Cellular Cardiology, 52(3), 701-10. https://doi.org/10.1016/j.yjmcc.2011.10.010
Mitra R, et al. The Transcriptional Coactivators, PGC-1α and Β, Cooperate to Maintain Cardiac Mitochondrial Function During the Early Stages of Insulin Resistance. J Mol Cell Cardiol. 2012;52(3):701-10. PubMed PMID: 22080103.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The transcriptional coactivators, PGC-1α and β, cooperate to maintain cardiac mitochondrial function during the early stages of insulin resistance. AU - Mitra,Riddhi, AU - Nogee,Daniel P, AU - Zechner,Juliet F, AU - Yea,Kyungmoo, AU - Gierasch,Carrie M, AU - Kovacs,Attila, AU - Medeiros,Denis M, AU - Kelly,Daniel P, AU - Duncan,Jennifer G, Y1 - 2011/10/20/ PY - 2011/07/27/received PY - 2011/09/30/revised PY - 2011/10/13/accepted PY - 2011/11/15/entrez PY - 2011/11/15/pubmed PY - 2012/7/10/medline SP - 701 EP - 10 JF - Journal of molecular and cellular cardiology JO - J. Mol. Cell. Cardiol. VL - 52 IS - 3 N2 - 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 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-1α(-/-) and Ob/Ob-PGC-1α(-/-) hearts lacked a mitochondrial biogenic response. PGC-1α 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-1α(-/-) mice and not in 8 week-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. SN - 1095-8584 UR - https://www.unboundmedicine.com/medline/citation/22080103/The_transcriptional_coactivators_PGC_1α_and_β_cooperate_to_maintain_cardiac_mitochondrial_function_during_the_early_stages_of_insulin_resistance_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2828(11)00437-8 DB - PRIME DP - Unbound Medicine ER -