Thyroid hormone receptor α in skeletal muscle is essential for T3‐mediated increase in energy expenditure

Nicolaisen, T; Klein, Anders Bue; Dmytriyeva, Oksana; Lund, J. W.; Ingerslev, Lars R.; Fritzen, Andreas M.; Carl, Christian S.; Lundsgaard, Anne‐Marie; Frost, Mikkel; Ma, Tao; Schjerling, Peter; Gerhart‐Hines, Zachary; Flamant, Frédéric; Gauthier, Karine; Larsen, Steen; Richter, Erik A.; Clemmensen, Christoffer

doi:10.1096/fj.202001258rr

Cited by 30 publications

(21 citation statements)

References 35 publications

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“…More importantly, the authors showed that T3 treated mice had elevated heat loss over the tail, suggesting that the animals actually needed to dissipate heat to maintain the body temperature, indicative of excess heat production in the periphery, presumably the muscle ( 22 ). Interestingly, however, it was also shown that blocking TRα1 signaling exclusively in the muscle also does not interfere with the elevation of body temperature upon thyroid hormone treatment ( 63 ).…”

Section: Central Effects Of Thmentioning

confidence: 99%

“…In the light of the recent studies, it seems plausible that TH primarily elevates body temperature by increasing the central set point as in pyrexia ( 22 , 62 ), which is at least partially fueled by peripheral TH action in muscle ( 22 , 39 ). However, the higher body temperature is observed in conditions with inactive BAT or browned WAT including Ucp1 knockout mice ( 22 , 62 ), as well as in mice with blocked skeletal muscle TRα1 signaling ( 63 ), which suggests that neither BAT nor muscle are absolutely required for the effect but likely can compensate for each other. Interestingly, alternative and UCP1-independent mechanisms of BAT thermogenesis could play a role in this context ( 69 , 70 ); however, these pathways were not upregulated in hyperthyroid mice ( 22 ).…”

Section: Open Questionsmentioning

confidence: 99%

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Thyroid hormones in the regulation of brown adipose tissue thermogenesis

Sentis

Oelkrug

Mittag

2021

Endocrine Connections

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A normal thyroid status is crucial for body temperature homeostasis, as thyroid hormone regulates both heat loss and conservation as well as heat production in thermogenic tissues. Brown adipose tissue (BAT) is the major site of non-shivering thermogenesis and an important target of thyroid hormone action. Thyroid hormone not only regulates the tissue’s sensitivity to sympathetic stimulation by norepinephrine, but also the expression of uncoupling protein 1, the key driver of BAT thermogenesis. Vice versa, sympathetic stimulation of BAT triggers the expression of deiodinase type II, an enzyme that enhances local thyroid hormone availability and signaling. This review summarizes the current knowledge on how thyroid hormone controls BAT thermogenesis, aiming to dissect the direct actions of the hormone in BAT and its indirect actions via the central nervous system, browning of white adipose tissue or heat loss over body surfaces. Of particular relevance is the apparent dose dependency of the observed effects, as we find that minor or moderate changes in thyroid hormone levels often have different effects as compared to high pharmacological doses. Moreover, we conclude that the more recent findings require a reevaluation of older studies, as key aspects such as heat loss or central BAT activation may not have received the necessary attention during the interpretation of these early findings. Finally, we provide a list of what we believe are the most relevant questions in the field that to date are still enigmatic and require further studies.

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Section: Central Effects Of Thmentioning

confidence: 99%

Section: Open Questionsmentioning

confidence: 99%

Thyroid hormones in the regulation of brown adipose tissue thermogenesis

Sentis

Oelkrug

Mittag

2021

Endocrine Connections

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“…We further examined the link between Six1 function and TH signaling in skeletal muscle by performing gene set enrichment analysis (GSEA) on the Six1-cKO gene expression profiling data of Sakakibara et al We generated two gene sets from the study of Nicolaisen et al (84), where the impact of T3 treatment and muscle-specific knockout of the thyroid hormone receptor alpha gene (Thra-cKO) was examined by RNA-seq. Specifically, we generated a first gene set representing genes whose expression is significantly lower in T3-treated muscle of Thra-cKO compared to wild-types, and a second one with the genes showing the opposite behavior, with expression higher in the Thra-cKO tissue.…”

Section: Thyroid Pathway Regulation Is Impacted Negatively In Six1 Loss-of-function Conditionsmentioning

confidence: 99%

“…The R script (including package versions and session information) used to analyze data and generate the figures is provided as supplementary files Code_S1. Gene set enrichment analysis was performed using the Sakakibara data and two gene sets from the Nicolaisen et al study (84). Briefly, RNA-seq data (read counts over genes) were downloaded from NCBI GEO accession GSE146336 and analyzed in R/Bioconductor using the edgeR package (100).…”

Section: Gene Expression Profiling Data Analysismentioning

confidence: 99%

Six1 Promotes Skeletal Muscle Thyroid Hormone Response through Regulation of the MCT10 Transporter

Blais

Yang

Chakroun

et al. 2021

Preprint

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The Six1 transcription factor is implicated in controlling the development of several tissue types, notably skeletal muscle. Six1 also contributes to muscle metabolism and its activity is associated with the fast-twitch, glycolytic phenotype. Six1 regulates the expression of certain genes of the fast muscle program by directly stimulating their transcription or indirectly acting through a long non-coding RNA. Under the hypothesis that additional mechanisms of action might be at play, a combined analysis of gene expression profiling and genome-wide location analysis data was performed. The Slc16a10 gene, encoding the thyroid hormone transmembrane transporter MCT10, was identified as a gene with a transcriptional enhancer directly bound by Six1 and requiring Six1 activity for full expression in adult mouse tibialis anterior, a predominantly fast-twitch muscle. Of the various thyroid hormone transporters, MCT10 mRNA was found to be the most abundant in skeletal muscle, and to have a stronger expression in fast-twitch compared to slow-twitch muscle groups. Loss-of-function of MCT10 in the tibialis anterior recapitulated the effect of Six1 on the expression of fast-twitch muscle genes and led to lower activity of a thyroid hormone receptor-dependent reporter gene. These results shed light on the molecular mechanisms controlling the tissue expression profile of MCT10 and identify modulation of the thyroid hormone signaling pathway as an additional mechanism by which Six1 influences skeletal muscle metabolism.

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“…In skeletal muscles, TH activity regulates the processes of myogenesis and muscle regeneration [ 38 , 39 ], contractile structure [ 40 ], energy expenditure [ 41 ], mitochondrial thermogenesis, fatty acid oxidation [ 42 ], glucose uptake [ 40 ], insulin responsiveness [ 43 ], and autophagy [ 44 ]. In the context of muscle fiber type specification, hyperthyroidism promotes fast-twitch muscle phenotypes, while hypothyroidism is associated with a switch toward slow-twitch phenotype [ 45 , 46 ].…”

Section: Introductionmentioning

confidence: 99%

Six1 promotes skeletal muscle thyroid hormone response through regulation of the MCT10 transporter

et al. 2021

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Background The Six1 transcription factor is implicated in controlling the development of several tissue types, notably skeletal muscle. Six1 also contributes to muscle metabolism and its activity is associated with the fast-twitch, glycolytic phenotype. Six1 regulates the expression of certain genes of the fast muscle program by directly stimulating their transcription or indirectly acting through a long non-coding RNA. We hypothesized that additional mechanisms of action of Six1 might be at play. Methods A combined analysis of gene expression profiling and genome-wide location analysis data was performed. Results were validated using in vivo RNA interference loss-of-function assays followed by measurement of gene expression by RT-PCR and transcriptional reporter assays. Results The Slc16a10 gene, encoding the thyroid hormone transmembrane transporter MCT10, was identified as a gene with a transcriptional enhancer directly bound by Six1 and requiring Six1 activity for full expression in adult mouse tibialis anterior, a predominantly fast-twitch muscle. Of the various thyroid hormone transporters, MCT10 mRNA was found to be the most abundant in skeletal muscle, and to have a stronger expression in fast-twitch compared to slow-twitch muscle groups. Loss-of-function of MCT10 in the tibialis anterior recapitulated the effect of Six1 on the expression of fast-twitch muscle genes and led to lower activity of a thyroid hormone receptor-dependent reporter gene. Conclusions These results shed light on the molecular mechanisms controlling the tissue expression profile of MCT10 and identify modulation of the thyroid hormone signaling pathway as an additional mechanism by which Six1 influences skeletal muscle metabolism.

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Thyroid hormone receptor α in skeletal muscle is essential for T3‐mediated increase in energy expenditure

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 30 publications

References 35 publications

Thyroid hormones in the regulation of brown adipose tissue thermogenesis

Thyroid hormones in the regulation of brown adipose tissue thermogenesis

Six1 Promotes Skeletal Muscle Thyroid Hormone Response through Regulation of the MCT10 Transporter

Six1 promotes skeletal muscle thyroid hormone response through regulation of the MCT10 transporter

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