Thyroid hormone interacts with PPARalpha and PGC-1 during mitochondrial maturation in sheep heart.
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-alpha (PPARalpha) and peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1). We tested the hypothesis that TH influences PPARalpha 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 PPARalpha and PGC-1 mRNA expression decreased from F to Con, while PGC-1 protein increased substantially and PPARalpha did not change. THY limited this mRNA response and attenuated the paradoxical postnatal PGC-1 protein elevation but did not alter mRNA levels for PPARalpha, nuclear respiratory factor-1 and hypoxia-inducible factor-1alpha. THY promotion in PPARalpha mRNA did not change PPARalpha protein or mRNA for PPARalpha 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 PPARalpha protein expression remains doubtful. Also, the paradoxical expression pattern between mRNA and protein, particularly for PGC-1, suggests a feedback control mechanism.
McClure
Timothy D
TD
University of Washington, School of Medicine, and Children's Hospital and Regional Medical Center W4841, 4800 Sand Point Way NE, Seattle, WA 98105, USA.
Young
Martin E
ME
Taegtmeyer
Heinrich
H
Ning
Xue-Han
XH
Buroker
Norman E
NE
López-Guisa
Jesús
J
Portman
Michael A
MA
D000818:Animals; D015153:Blotting, Western; D045304:Cytochromes c / Q000378:metabolism; D017931:DNA Primers; D003576:Electron Transport Complex IV / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000254:growth & development*; D066298:In Vitro Techniques; D007700:Kinetics; D008929:Mitochondria, Heart / Q000201:enzymology / Q000502:physiology*; D010101:Oxygen Consumption / Q000187:drug effects; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D013963:Thyroid Hormones / Q000502:physiology*; D013965:Thyroidectomy; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D017931:DNA Primers; D047493:PPAR alpha; D013963:Thyroid Hormones; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D012313:RNA; D045304:Cytochromes c; D003576:Electron Transport Complex IV