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Thyroid hormone interacts with PPAR and PGC-1 during mitochondrial maturation in sheep heart

¹University of Washington, School of Medicine, and Children's Hospital and Regional Medical Center, Seattle, Washington; and ²University of Texas Science Center, Brown Foundation Institute of Molecular Medicine and ³Medical School, Houston Texas

Submitted 9 May 2005 ; accepted in final form 12 July 2005

Thyroid hormone (TH) promotes cardiac mitochondrial maturation and substrate metabolism after birth. This regulation involves ligand-dependent binding of nuclear TH receptors to target gene elements. TH also putatively controls genes indirectly by modulating transcription and/or translation of other nuclear steroid receptors and coactivators, such as peroxisome proliferator-activated receptor- (PPAR) and peroxisome proliferator-activated receptor- coactivator-1 (PGC-1). We tested the hypothesis that TH influences PPAR and PGC-1 regulation of metabolic genes during postnatal maturation in sheep heart in vivo. We measured their mRNAs and/or protein levels and downstream targets in left ventricle from lambs: fetal (F), 30-day-old after postnatal thyroidectomy (THY), and 30-day-old euthyroid (Con). Both PPAR and PGC-1 mRNA expression decreased from F to Con, while PGC-1 protein increased substantially and PPAR did not change. THY limited this mRNA response and attenuated the paradoxical postnatal PGC-1 protein elevation but did not alter mRNA levels for PPAR, nuclear respiratory factor-1 and hypoxia-inducible factor-1. THY promotion in PPAR mRNA did not change PPAR protein or mRNA for PPAR target genes, pyruvate-dehydrogenase kinase 4 (PDK4) and muscle type carnitine palmitoyltransferase I (mCPTI). THY reduction in PGC-1 protein occurred, while reducing cytochrome c oxidase and cytochrome c content and decreasing cardiac maximal inherent respiratory capacity. These data imply that TH modulates mitochondrial maturation partly through posttranscriptional control of PGC-1, while any important regulation of PDK4 and mCPTI by change in PPAR protein expression remains doubtful. Also, the paradoxical expression pattern between mRNA and protein, particularly for PGC-1, suggests a feedback control mechanism.

carnitine palmitoyltransferase I; fatty acid metabolism; mitochondrial biogenesis

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