Mct8-Deficient Mice Have Increased Energy Expenditure and Reduced Fat Mass That Is Abrogated by Normalization of Serum T3 Levels

Cosmo, Caterina Di; Liao, Xiao Hui; Ye, Honggang; Ferrara, Alfonso Massimiliano; Weiss, Roy E.; Refetoff, Samuel; Dumitrescu, Alexandra M.

doi:10.1210/en.2013-1150

Cited by 41 publications

(31 citation statements)

References 32 publications

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“…Mct8KO mice had decreased T4 and rT3 levels but increased TSH and slightly elevated T3 concentrations compared with WT mice ( Fig. 1 ), as reported previously ( 17 – 19 , 30 ). Consistent with previous data ( 19 ), Mct8D1D2KO mice had elevated T4, rT3, and TSH concentrations at all ages compared with WT and Mct8KO mice.…”

Section: Resultssupporting

confidence: 88%

An Essential Physiological Role for MCT8 in Bone in Male Mice

et al. 2017

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T3 is an important regulator of skeletal development and adult bone maintenance. Thyroid hormone action requires efficient transport of T4 and T3 into target cells. We hypothesized that monocarboxylate transporter (MCT) 8, encoded by Mct8 on the X-chromosome, is an essential thyroid hormone transporter in bone. To test this hypothesis, we determined the juvenile and adult skeletal phenotypes of male Mct8 knockout mice (Mct8KO) and Mct8D1D2KO compound mutants, which additionally lack the ability to convert the prohormone T4 to the active hormone T3. Prenatal skeletal development was normal in both Mct8KO and Mct8D1D2KO mice, whereas postnatal endochondral ossification and linear growth were delayed in both Mct8KO and Mct8D1D2KO mice. Furthermore, bone mass and mineralization were decreased in adult Mct8KO and Mct8D1D2KO mice, and compound mutants also had reduced bone strength. Delayed bone development and maturation in Mct8KO and Mct8D1D2KO mice is consistent with decreased thyroid hormone action in growth plate chondrocytes despite elevated serum T3 concentrations, whereas low bone mass and osteoporosis reflects increased thyroid hormone action in adult bone due to elevated systemic T3 levels. These studies identify an essential physiological requirement for MCT8 in chondrocytes, and demonstrate a role for additional transporters in other skeletal cells during adult bone maintenance.

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Section: Resultssupporting

confidence: 88%

An Essential Physiological Role for MCT8 in Bone in Male Mice

et al. 2017

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“…Cosmo et al reported that TH uptake by skeletal muscle can occur independently of monocarboxylate transporter 8 (Mct8). However, they found enhanced TH action, T 3 content, and glucose metabolism in Mct8 knockout mice [32]. We speculate that TTR might maintain the TH content in Mct8 knockout mice and, hence, normal muscle metabolism and development.…”

Section: Discussionmentioning

confidence: 71%

Transthyretin Maintains Muscle Homeostasis through the Novel Shuttle Pathway of Thyroid Hormones during Myoblast Differentiation

Lee

Shaikh

Choi

et al. 2019

Cells

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Skeletal muscle, the largest part of the total body mass, influences energy and protein metabolism as well as maintaining homeostasis. Herein, we demonstrate that during murine muscle satellite cell and myoblast differentiation, transthyretin (TTR) can exocytose via exosomes and enter cells as TTR- thyroxine (T4) complex, which consecutively induces the intracellular triiodothyronine (T3) level, followed by T3 secretion out of the cell through the exosomes. The decrease in T3 with the TTR level in 26-week-old mouse muscle, compared to that in 16-week-old muscle, suggests an association of TTR with old muscle. Subsequent studies, including microarray analysis, demonstrated that T3-regulated genes, such as FNDC5 (Fibronectin type III domain containing 5, irisin) and RXRγ (Retinoid X receptor gamma), are influenced by TTR knockdown, implying that thyroid hormones and TTR coordinate with each other with respect to muscle growth and development. These results suggest that, in addition to utilizing T4, skeletal muscle also distributes generated T3 to other tissues and has a vital role in sensing the intracellular T4 level. Furthermore, the results of TTR function with T4 in differentiation will be highly useful in the strategic development of novel therapeutics related to muscle homeostasis and regeneration.

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“…These efforts were severely hampered by the fact that information regarding molecular and cellular abnormalities in the CNS of affected patients are still scarce, and that a suitable animal model replicating the phenotype of human MCT8 deficiency was not available. Although mice deficient in MCT8 revealed important aspects regarding the role of MCT8 in peripheral tissues, such as liver, kidneys, and thyroid gland (11)(12)(13)(31)(32)(33), Mct8 KO mice did not show any overt neurological symptoms, calling this mouse model into question as an adequate model system for AHDS.…”

Section: Discussionmentioning

confidence: 99%

Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis

Mayerl¹,

Müller²,

Bauer³

et al. 2014

J. Clin. Invest.

243

242

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Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of Mct8 (Mct8 KO) faithfully replicates AHDS-associated endocrine abnormalities; however, unlike patients, these animals do not exhibit neurological impairments. While transport of the active form of TH (T3) across the blood-brain barrier is strongly diminished in Mct8 KO animals, prohormone (T4) can still enter the brain, possibly due to the presence of T4-selective organic anion transporting polypeptide (OATP1C1). Here, we characterized mice deficient for both TH transporters, MCT8 and OATP1C1 (Mct8/Oatp1c1 DKO). Mct8/Oatp1c1 DKO mice exhibited alterations in peripheral TH homeostasis that were similar to those in Mct8 KO mice; however, uptake of both T3 and T4 into the brains of Mct8/Oatp1c1 DKO mice was strongly reduced. Evidence of TH deprivation in the CNS of Mct8/Oatp1c1 DKO mice included highly decreased brain TH content as well as altered deiodinase activities and TH target gene expression. Consistent with delayed cerebellar development and reduced myelination, Mct8/Oatp1c1 DKO mice displayed pronounced locomotor abnormalities. Intriguingly, differentiation of GABAergic interneurons in the cerebral cortex was highly compromised. Our findings underscore the importance of TH transporters for proper brain development and provide a basis to study the pathogenic mechanisms underlying AHDS. IntroductionMonocarboxylate transporter 8 (MCT8) is a specific thyroid hormone (TH) transporter that facilitates the passage of the prohormone 3,3′,5,5′-tetraiodothyronine (T4; also known as thyroxine) and the receptor active form, 3,3′,5-triiodothyronine (T3), across the plasma membrane (1). MCT8 is encoded by SLC16A2 (hereafter MCT8) located on human chromosome Xq13.2. Inactivating mutations and deletions in MCT8 result in a distinct clinical picture known as Allan-Herndon-Dudley syndrome (AHDS) (2-5).All affected patients manifest a severe form of psychomotor retardation composed of central hypotonia, spastic tetraplegia, lack of speech development, severe intellectual deficits, and global developmental delays. In addition to the pronounced neurological symptoms, patients exhibit characteristic changes in the serum TH profile, with highly elevated T3 and lowered T4 concentrations. Since 2004, more than 45 families with 125 affected individuals have been reported in the literature, and 1% of cases with the diagnosis of X-linked mental retardation have been estimated to be associated with mutations in MCT8 (6). However, by which pathogenic mechanisms MCT8 deficiency causes AHDS remains largely unknown.MCT8 is present in many organs, such as liver, kidneys, pituitary, and thyroid gland, and is also widely expressed in the CNS. Studies in mouse and human brain tissues revealed MCT8 expression in distinct neuronal populations, with the highest mRNA levels in neo-and allocortical structures (e.g., cerebral cor...

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Mct8-Deficient Mice Have Increased Energy Expenditure and Reduced Fat Mass That Is Abrogated by Normalization of Serum T3 Levels

Cited by 41 publications

References 32 publications

An Essential Physiological Role for MCT8 in Bone in Male Mice

An Essential Physiological Role for MCT8 in Bone in Male Mice

Transthyretin Maintains Muscle Homeostasis through the Novel Shuttle Pathway of Thyroid Hormones during Myoblast Differentiation

Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis

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