Abstract
3,5-diiodo-l-thyronine (T2) is an endogenous derivative of thyroid hormone that has been suggested to regulate energy expenditure, resting metabolic rate and oxygen consumption with a mechanism that involves the activation of mitochondrial function. In this study, we focused on the cardiac effects of T2, which have been poorly investigated so far, by using both in vitro and ex vivo models. As a comparison, the response to T3 and T4 was also determined. Rat cardiomyoblasts (H9c2 cells) were used to determine T2, T3, and T4 uptake by high-performance liquid chromatography–tandem mass spectrometry. In the same experimental model, MTT test, crystal violet staining, and glucose consumption were investigated, using T2 concentrations ranging from 0.1 to 10 µM. To assess cardiac functional effects, isolated working rat hearts were perfused with T2, T3, or T4 in Krebs-Ringer buffer, and the hemodynamic variables were recorded. T2 was taken up by cardiomyoblasts, and in cell lysate T2 levels increased slowly over time, reaching higher concentrations than in the incubation medium. T2 significantly decreased MTT staining at 0.5–10 µM concentration (P < 0.05). Crystal violet staining confirmed a reduction of cell viability only upon treatment with 10 µM T2, while equimolar T3 and T4 did not share this effect. Glucose consumption was also significantly affected as indicated by glucose uptake being increased by 24 or 35% in cells exposed to 0.1 or 1.0 µM T2 (P < 0.05 in both cases). On the contrary, T3 did not affect glucose consumption which, in turn, was significantly reduced by 1 and 10 µM T4 (−24 and −41% vs control, respectively, P < 0.05 and P < 0.01). In the isolated perfused rat heart, 10 µM T2 produced a slight and transient reduction in cardiac output, while T3 and T4 did not produce any hemodynamic effect. Our findings indicate that T2 is taken up by cardiomyoblasts, and at 0.1–1.0 µM concentration it can modulate cardiac energy metabolism by increasing glucose consumption. Some evidence of toxicity and a transient impairment of contractile performance are observed only at 10 µM concentration. These effects appear to be specific for T2, since they are not reproduced by T3 or T4.
Highlights
3,5-Diiodo-l-thyronine (T2), an endogenous metabolite of thyroid hormones (TH), has been described as a peripheral mediator of several TH metabolic effects [1]
T2 concentration increased over time reaching a value of about 14 nM (7 pmol/ well) after 24 h, while in medium steady state concentration was reached after 6 h, and it averaged about 110 nM (55 pmol/well)
Similar results were obtained in the presence of 50 nM T3 or T4, whose cellular uptake after 24 h was on the order of 10 and 2% of the medium concentration, respectively
Summary
3,5-Diiodo-l-thyronine (T2), an endogenous metabolite of thyroid hormones (TH), has been described as a peripheral mediator of several TH metabolic effects [1]. Conversion of 3,5,3′-triiodothyronine (T3) to T2 has not yet been demonstrated in vitro, indirect evidence indicates that T2 is, formed from T3 in vivo, through deiodination [2] Both T2 and T3 increase resting metabolic rate, but the response to T2 shows a more rapid onset [3]. [10], T2 prevented body weight gain in rats fed with a high-fat diet, without inducing T3-related undesirable side effects, namely tachycardia, cardiac hypertrophy, and decreased TSH levels In this models, T2 stimulated mitochondrial uncoupling, decreased ATP synthesis, and increased hepatic fatty acid oxidation rate, counteracting obesity. Chronic administration of a low T2 dosage to two healthy volunteers increased resting metabolic rate and decreased body weight, by inducing a reduction in steatosis and in the total serum cholesterol levels, without affecting cardiac function [14]. In this study we explored the functional, metabolic, and toxic effects of T2 using both in vitro and ex vivo models of cardiac preparations
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