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

Background-The signal transduction mechanism linking mitochondrial ATP synt hesis with cytosolic ATP utilization in heart changes during postnatal deve lopment in vivo, This maturational process occurs in parallel with accumula tion of mitochondrial adenine nucleotide translocator (ANT), which provides a possible site for respiratory control. We postulated that thyroid hormon e regulates these maturational processes. Methods and Results-We used P-31 MR spectroscopy to determine the relations hip between myocardial high-energy phosphates, phosphocreatine, and ADP and oxygen consumption (M(V)over dot O-2) during epinephrine stimulation in 32 - to 40-day-old lambs thyroidectomized after birth (THY) and age-matched co ntrols. Steady-state protein and mRNA levels for ANT isoforms and beta-F-1- ATPase were assessed from left ventricular tissues by Western and Northern blotting. With greater doses of epinephrine, THY attained lower peak M(V)ov er dot O-2 than controls (P < 0.05), Controls maintained high-energy phosph ate levels, unlike THY, which demonstrated significantly decreased phosphoc reatine/ATP and increased cytosolic ADP despite lower peak M(V)over dot O-2 . NO significant differences in beta-F-1-ATPase protein or mRNA occurred be tween groups. However, ANT isoform mRNA levels were 2-fold greater and prot ein levels 4-fold greater in control hearts. Conclusions-These data imply that the maturational shift away from ADP-medi ated respiratory control is regulated by thyroid hormone in vivo. Specific thyroid-modulated increases in ANT mRNA and protein imply that this regulat ion occurs in part at a pretranslational level.