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 expressed in the mammalian heart under the control of a developmentally regulated program. ssTnI is expressed first in embryonic and fetal heart, and is then downregulated by an unknown mechanism after birth. Unlike other contractile protein genes, ssTnI is not re-expressed during hypertrophy or end-stage heart failure in rats and humans. In the present study, we also show that ssTnI re-expression does not occur in hypertrophic mouse heart. To investigate ssTnI downregulation further, cTnI knockout mice were used to examine a possible role for thyroid hormone. Northern blot analysis of euthyroid animals showed a time-dependent loss of ssTnI mRNA that was similar for wild-type, heterozygous and homozygous cTnI mutant mice. In cTnI null mice made hyperthyroid by l -thyroxine, the duration of ssTnI expression assessed by both mRNA and protein content was abbreviated compared with the euthyroid group. Hyperthyroid cTnI null mice also died significantly earlier than euthyroids (postnatal day 14 v day 18). In cTnI null mice made hypothyroid by addition of phenylthiouracil to the drinking water, ssTnI expression was prolonged and mice survived until day 20 or 21. Overall, the results indicate that inactivation of the ssTnI gene occurs even in the absence of cTnI mRNA and protein indicating that these are not critical signals for ssTnI down regulation in the heart. In contrast, thyroid hormone influences the time course of ssTnI expression and the life span of cTnI null mice probably through a transcriptional regulation of ssTnI in the heart.
Huang
X
X
Department of Medical Physiology, Texas A&M University System Health Science Center, College Station, TX 77843, USA. xupei@tamu.edu
Lee
K J
KJ
Riedel
B
B
Zhang
C
C
Lemanski
L F
LF
Walker
J W
JW
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D006332:Cardiomegaly; D015536:Down-Regulation; D005786:Gene Expression Regulation; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D013889:Thiouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D013963:Thyroid Hormones / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism; D013997:Time Factors; D019210:Troponin I / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*
D020033:Protein Isoforms; D012333:RNA, Messenger; D013963:Thyroid Hormones; D019210:Troponin I; C060320:6-phenylthiouracil; D013889:Thiouracil; D013974:Thyroxine