Thyroid hormone regulates slow skeletal troponin I gene inactivation in cardiac troponin I null mouse hearts

Two main troponin I genes, cardiac (cTnI) and slow skeletal (ssTnI), are ex pressed in the mammalian heart under the control of a developmentally regul ated program, ssTnI is expressed first in embryonic and fetal heart, and is then downregulated by an unknown mechanism after birth. Unlike other contr actile protein genes, ssTnI is not re-expressed during hypertrophy or end-s tage heart failure in rats and humans, In the present study, we also show t hat ssTnI re-expression does not occur in hypertrophic mouse heart. To inve stigate ssTnI downregulation further, cTnI knockout mice were used to exami ne a possible role for thyroid hormone, Northern blot analysis of euthyroid animals showed a time-dependent loss of ssTnI mRNA that was similar for wi ld-type, heterozygous and homozygous cTnI mutant mice. In cTnI null mice ma de hyperthyroid by L-thyroxine, the duration of ssTnI expression assessed b y both mRNA and protein content was abbreviated compared with the euthyroid group, Hyperthyroid cTnI null mice also died significantly earlier than eu thyroids (postnatal day 14 v day 18), In cTnI null mice made hypothyroid by addition of phenylthiouracil to the drinking water, ssTnI expression was p rolonged and mice survived until day 20 or 21, Overall, the results indicat e that inactivation of the ssTnI gene occurs even in the absence of cTnI mR NA and protein indicating that these are not critical signals for ssTnI dow n regulation in the heart. In contrast, thyroid hormone influences the time course of ssTnI expression and the life span of cTnI null mice probably th rough a transcriptional regulation of ssTnI in the heart. (C) 2000 Academic Press.