Effect of Triiodothyroacetic Acid Treatment in Mct8 Deficiency: A Word of Caution

[Background]: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell membrane transporter. Mutations in the MCT8 gene lead to profound psychomotor retardation and abnormal thyroid hormone serum levels with low thyroxine (T4) and high triiodothyronine (T3). Currently, therapeutic options for patients are limited. Triiodothyroacetic acid (TRIAC) has potential therapeutic value. The aim of this study was to evaluate the effects and efficacy of therapeutic doses of TRIAC on Mct8-deficient mice (Mct8KO).[Methods]: Wild-type (Wt) and Mct8KO mice were treated with 30 ng TRIAC/g BW/day, given in drinking water, from postnatal day 21 to 30. TRIAC, T4 and T3 levels in plasma, as well as T3 and TRIAC content in the cerebral cortex and striatum were measured by specific radioimmunoassays. The activities of deiodinases 1 and 2 were measured in liver and cortex. The effect of TRIAC treatment in the expression of T3-dependent genes was measured in the heart, cerebral cortex and striatum.[Results]: Plasma TRIAC concentration were the same in Wt and Mct8KO animals after treatment. TRIAC treatment greatly decreased plasma T4 in Wt and Mct8KO mice, and reduced T3 to normal levels in the Mct8KO. Deiodinase 1 activity and gene expression in the liver increased while it did not have any effect on the expression of Serca2a in the heart. TRIAC treatment did not induce the expression of T3-dependent genes in the cerebral cortex or striatum but further decreased expression of Flywch2 in the cortex and Aldh1a1 and Flywch2 in the striatum. Direct measurements of TRIAC and T3 content in the cortex and striatum revealed a decrease in T3 after treatment with no significant increase in the level of endogenous TRIAC.[Conclusions]: Therapeutic doses of TRIAC in Mct8KO mice restored plasma T3 levels but severely decreased T4 levels. TRIAC has a direct effect on deiodinase 1 in the liver and does not have an effect on gene expression in the heart. The increase in the plasma TRIAC levels after treatment is not sufficient to increase TRIAC levels in the brain and to promote the expression of T3-dependent genes in brain cells. Instead, it leads to a state of brain hypothyroidism with reduced T3 content.This work was supported by Grants from the Mehuer Foundation and the Seville's College of Pharmacists, Ramón Areces Foundation (CIVP16A1805), Spanish Ministry of Economy and Competitiveness (SAF2011-25608, SAF2014-54919-R, SAF 2012-32491) and S2010/BMD-2423 from CAM and under the frame of E‑Rare‑2 and the “Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III” under the frame of the ERA-Net for Research on Rare Diseases. S.B.-L. is recipient of a predoctoral fellowship and contract from the FPI program of the Plan Nacional de I+D+i. The cost of this publication has been paid in part by FEDER funds.Peer reviewe