EFFECT OF HYPOTHYROIDISM ON THE EXPRESSION OF CYTOCHROME-C AND CYTOCHROME-C-OXIDASE IN HEART AND MUSCLE DURING DEVELOPMENT

The effect of thyroid hormone on the expression of mitochondrial prote ins was evaluated during development by measuring cytochrome c oxidase (CYTOX) activity and cytochrome c protein and mRNA levels in heart an d skeletal muscle of control and hypothyroid rats. Animals were killed at the late fetal, early, and late postnatal stages up to 56 days of age. In heart, CYTOX activity increased 2.3-fold above the fetal level throughout development, most of which occurred prior to 2 days of age . No increase was observed in muscle. CYTOX activity was reduced in hy pothyroid animals throughout development in heart compared to controls (by 50% at 56 days), but in muscle no effect of hypothyroidism was ob served. In muscle and heart 4- and 1.5-fold increases in cytochrome c above the fetal level were evident by 1 day of age, with further incre ases to 8.5- and 2.7-fold by 56 days, respectively. The increase in cy tochrome c differed from the increase in CYTOX, indicating changes in mitochondrial composition. Hypothyroidism reduced cytochrome c in musc le by 30-35% at 56 days, but had no effect in heart, indicating a musc le type-specific effect of thyroid hormone on cytochrome c protein exp ression. Cytochrome c mRNA increased rapidly to 4-5 fold above the fet al level in both heart and muscle by 6 h post-partum. Between 7 and 56 days of age, further increases to 6- and 25-fold were observed in mus cle and heart, respectively. In muscle, the 6-fold developmental incre ase in mRNA paralleled that of the protein, suggesting transcriptional regulation. In heart, the large 25-fold increase in cytochrome c mRNA far exceeded that of cytochrome c protein between the fetal stage and 56 days (2.7-fold), indicating post-transcriptional regulation. Hypot hyroidism reduced cytochrome c protein in muscle, but had no effect on mRNA. In contrast, hypothyroidism reduced cytochrome c mRNA in heart, without a change in cytochrome c protein. Thus, both transcriptional and post-transcriptional effects of thyroid hormone on the expression of mitochondrial proteins in the two types of striated muscle were evi dent. These effects were tissue-specific, developmentally-regulated, a nd uncoordinated among nuclear-encoded protei ns. Further, large devel opmental increases in cytochrome c mRNA and protein levels can occur b etween the fetal stage and early post-natal time points (6-24 h) in bo th heart and muscle.