title: 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 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.affiliation: Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Riddhi
authors.initials: R
authors.lastname: Mitra
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Nogee
authors.forename: Juliet F
authors.initials: JF
authors.lastname: Zechner
authors.forename: Kyungmoo
authors.initials: K
authors.lastname: Yea
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Gierasch
authors.forename: Attila
authors.initials: A
authors.lastname: Kovacs
authors.forename: Denis M
authors.initials: DM
authors.lastname: Medeiros
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Duncan
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013599:Systole / Q000502:physiology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D005947:Glucose
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