Altered glucose metabolism in heart is an important characteristic of cardiovascular and metabolic disease. Since thyroid hormones have major effects on peripheral metabolism, we examined the metabolic effects of heart-selective increase in 3,5,3`-triiodothyronine (T3) using transgenic mice expressing human type 2 iodothyronine deiodinase (D2) under the control of the α-myosin heavy chain (MHC) promoter (MHC-D2). Hyperinsulinmic-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 2-fold in MHC-D2 mice. Myocardial lipid levels were also elevated in MHC-D2 mice, suggesting an overall upregulation 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 6-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.
Cardiac expression of human type 2 Iodothyronine deiodinase increases glucose metabolism and protects against Doxorubicin-induced cardiac dysfunction in male mice.
Hong EG, Kim BW, Young Jung D, Hun Kim J, Yu T, Seixas Da Silva W, Friedline RH, Bianco SD, Seslar SP, Wakimoto H, Berul CI, Russell KS, Won Lee K, Larsen PR, Bianco AC, Kim JK. Endocrinology. October, 2013. PMID: 23861374.