Cardiac expression of human type 2 iodothyronine deiodinase increases glucose metabolism and protects against doxorubicin-induced cardiac dysfunction in male mice

Eun Gyoung Hong, Brian W. Kim, Dae Young Jung, Jong Hun Kim, Tim Yu, Wagner Seixas Da Silva, Randall H. Friedline, Suzy D. Bianco, Stephen P. Seslar, Hiroko Wakimoto, Charles I. Berul, Kerry S. Russell, Ki Won Lee, P. Reed Larsen, Antonio C. Bianco, Jason K. Kim

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Abstract

Altered glucose metabolism in the heart is an important characteristic of cardiovascular and metabolic disease. Because thyroid hormones have major effects on peripheral metabolism, we examined the metabolic effects of heart-selective increase in T3 using transgenic mice expressing human type 2 iodothyronine deiodinase (D2) under the control of the α-myosin heavy chain promoter (MHC-D2). Hyperinsulinemic-euglycemic clamps showed normal whole-body glucose disposal but increased hepatic insulin action in MHC-D2 mice as compared to wild-type (WT) littermates. Insulin-stimulated glucose uptake in heart was not altered, but basal myocardial glucose metabolism was increased by more than two-fold in MHC-D2 mice. Myocardial lipid levels were also elevated in MHC-D2 mice, suggesting an overall up-regulation of cardiac metabolism in these mice. The effects of doxorubicin (DOX) treatment on cardiac function and structure were examined using M-mode echocardiography. DOX treatment caused a significant reduction in ventricular fractional shortening and resulted in more than 50% death in WT mice. In contrast, MHC-D2 mice showed increased survival rate after DOX treatment, and this was associated with a six-fold increase in myocardial glucose metabolism and improved cardiac function. Myocardial activity and expression of AMPK, GLUT1, and Akt were also elevated in MHC-D2 and WT mice following DOX treatment. Thus, our findings indicate an important role of thyroid hormone in cardiac metabolism and further suggest a protective role of glucose utilization in DOX-mediated cardiac dysfunction.

Original languageEnglish (US)
Pages (from-to)3937-3946
Number of pages10
JournalEndocrinology
Volume154
Issue number10
DOIs
StatePublished - Oct 1 2013

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ASJC Scopus subject areas

  • Endocrinology

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Hong, E. G., Kim, B. W., Jung, D. Y., Kim, J. H., Yu, T., Da Silva, W. S., Friedline, R. H., Bianco, S. D., Seslar, S. P., Wakimoto, H., Berul, C. I., Russell, K. S., Lee, K. W., Larsen, P. R., Bianco, A. C., & Kim, J. K. (2013). Cardiac expression of human type 2 iodothyronine deiodinase increases glucose metabolism and protects against doxorubicin-induced cardiac dysfunction in male mice. Endocrinology, 154(10), 3937-3946. https://doi.org/10.1210/en.2012-2261