Cardiac glucose utilization in mice with mutated α- and β-thyroid hormone receptors

Abstract

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.

A Mutation in the Thyroid Hormone Receptor Alpha Gene

“…15 The bradycardia and low blood pressure seen in our patient have also been observed in murine models and may reflect myocardial thyroid hormone resistance or central autonomic dysfunction. 14,17 Free triiodothyronine levels in our patient were either high normal or slightly raised, as in TRαPV mice, 18 with circulating free thyroxine being disproportionately low, resulting in a markedly abnormal, reduced ratio of free thyroxine to free triiodothyronine. This abnormal ratio, together with very low reverse triiodothyronine levels, may reflect altered metabolism of thyroid hormone in our patient.…”

Muscle as a “Mediator” of Systemic Metabolism

“…Increased TR transcriptional activity in muscle is accompanied by a switch from fast- to slow-twitch fiber type (Salvatore et al, 2014) (Figure 1B). Genetic models of TRs have also implicated TR in cardiac metabolism and function (Esaki et al, 2004; Hyyti et al, 2008; Kahaly and Dillmann, 2005; Pazos-Moura et al, 2000) (Table 1). Indeed, decreased thyroid hormone activity has been correlated with worsening heart failure, but efforts to improve heart function with TR agonists have been unsuccessful and are associated with adverse side effects (Burris et al, 2013).…”

Genetic and pharmacological manipulations of the serotonergic system in early life: neurodevelopmental underpinnings of autism-related behavior

“…5-HTT −/− rats and mice show a distorted or nearly absent barrel pattern in cortical layer IV (Persico et al, 2000) (Miceli et al, submitted). Furthermore, Esaki et al (2004) demonstrated that glucose uptake in the barrel cortex is significantly reduced in these mice, implying that the barrel cortex is also functionally impaired (Esaki et al, 2004). These changes may be related to altered (netrin-1-dependent) guidance of thalamocortical afferents (TCAs), which project to the barrels [see section The Serotonin Transporter (5-HTT)].…”