University of Massachusetts Medical School Faculty Publications

Title

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

UMMS Affiliation

Program in Molecular Medicine; Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine

Publication Date

10-2013

Document Type

Article

Subjects

AMP-Activated Protein Kinases; Animals; Antibiotics, Antineoplastic; Doxorubicin; Glucose; Glucose Clamp Technique; Glucose Transporter Type 1; Heart Ventricles; Humans; *Insulin Resistance; Iodide Peroxidase; Lipid Metabolism; Liver; Male; Mice; Mice, Transgenic; Proto-Oncogene Proteins c-akt; Survival Analysis; Triiodothyronine; Ventricular Dysfunction; induced

Disciplines

Cardiology | Cellular and Molecular Physiology | Endocrinology | Endocrinology, Diabetes, and Metabolism

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 alpha-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.

Rights and Permissions

Citation: Endocrinology. 2013 Oct;154(10):3937-46. doi: 10.1210/en.2012-2261. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Endocrinology

PubMed ID

23861374