Cardiac glucose utilization in mice with mutated alpha- and beta-thyroid hormone receptors.
Abnormal thyroid function is usually associated with altered cardiac function. Mutations in the thyroid hormone (TH)-binding region of the TH beta-receptor (TRbeta) that eliminate its TH-binding ability lead to the thyroid hormone resistance syndrome (RTH) in humans, which is characterized by high blood TH levels, goiter, hyperactivity, and tachycardia. Mice with "knock-in" mutations in the TH alpha-receptor (TRalpha) or TRbeta that remove their TH-binding ability have been developed, and those with the mutated TRbeta (TRbeta(PV/PV)) appear to provide a model for RTH. These two types of mutants show different effects on cerebral energy metabolism, e.g., negligible change in glucose utilization (CMR(Glc)) in TRbeta(PV/PV) mice and markedly reduced CMR(Glc), like that found in cretinous rats, in the mice (TRalpha(PV/+)) with the knock-in mutation of the TRalpha gene. Studies in knockout mice have indicated that the TRalpha may also influence heart rate. Because mutations in both receptor genes appear to affect some parameters of cardiac function and because cardiac functional activity and energy metabolism are linked, we measured heart glucose utilization (HMR(Glc)) in both the TRbeta(PV/PV) and TRalpha(PV/+) mutants. Compared with values in normal wild-type mice, HMR(Glc) was reduced (-77 to -95%) in TRalpha(PV/+) mutants and increased (87 to 340%) in TRbeta(PV/PV) mutants, the degree depending on the region of the heart. Thus the TRalpha(PV/+) and TRbeta(PV/PV) mutations lead, respectively, to opposite effects on energy metabolism in the heart that are consistent with the bradycardia seen in hypothyroidism and the tachycardia associated with hyperthyroidism and RTH.
Laboratory of Cerebral Metabolism, National Institute of Mental Health, Bldg. no. 36, Rm. 1A-07, 36 Convent Drive MSC 4030, Bethesda, MD 20892, USA.
Takanori
T
Esaki
Hideyo
H
Suzuki
Michelle
M
Cook
Kazuaki
K
Shimoji
Sheue-Yann
SY
Cheng
Louis
L
Sokoloff
Jacques
J
Nunez
D000818:Animals; D004734:Energy Metabolism / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics*; D037042:Thyroid Hormone Receptors beta; D014018:Tissue Distribution
D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D005947:Glucose