Thyroid hormone coordinates respiratory control maturation and adenine nucleotide translocator expression in heart in vivo

Abstract

Background - The signal transduction mechanism linking mitochondrial ATP synthesis with cytosolic ATP utilization in heart changes during postnatal development in vivo. This maturational process occurs in parallel with accumulation of mitochondrial adenine nucleotide translocator (ANT), which provides a possible site for respiratory control. We postulated that thyroid hormone regulates these maturational processes. Methods and Results - We used 31P MR spectroscopy to determine the relationship between myocardial high-energy phosphates, phosphocreatine, and ADP and oxygen consumption (MVo2) during epinephrine stimulation in 32- to 40-day-old lambs thyroidectomized after birth (THY) and age-matched controls. Steady-state protein and mRNA levels for ANT isoforms and β-F1-ATPase were assessed from left ventricular tissues by Western and Northern blotting. With greater doses of epinephrine, THY attained lower peak MVo2 than controls (P<0.05). Controls maintained high-energy phosphate levels, unlike THY, which demonstrated significantly decreased phosphocreatine/ATP and increased cytosolic ADP despite lower peak MVo2. No significant differences in β-F1-ATPase protein or mRNA occurred between groups. However, ANT isoform mRNA levels were 2-fold greater and protein levels 4-fold greater in control hearts. Conclusions - These data imply that the maturational shift away from ADP-mediated respiratory control is regulated by thyroid hormone in vivo. Specific thyroid-modulated increases in ANT mRNA and protein imply that this regulation occurs in part at a pretranslational level.