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

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 gene...

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Autores principales: Girgis, John, Yang, Dabo, Chakroun, Imane, Liu, Yubing, Blais, Alexandre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607597/
https://www.ncbi.nlm.nih.gov/pubmed/34809717
http://dx.doi.org/10.1186/s13395-021-00281-6
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author Girgis, John
Yang, Dabo
Chakroun, Imane
Liu, Yubing
Blais, Alexandre
author_facet Girgis, John
Yang, Dabo
Chakroun, Imane
Liu, Yubing
Blais, Alexandre
author_sort Girgis, John
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13395-021-00281-6.
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spelling pubmed-86075972021-11-22 Six1 promotes skeletal muscle thyroid hormone response through regulation of the MCT10 transporter Girgis, John Yang, Dabo Chakroun, Imane Liu, Yubing Blais, Alexandre Skelet Muscle Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13395-021-00281-6. BioMed Central 2021-11-19 /pmc/articles/PMC8607597/ /pubmed/34809717 http://dx.doi.org/10.1186/s13395-021-00281-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Girgis, John
Yang, Dabo
Chakroun, Imane
Liu, Yubing
Blais, Alexandre
Six1 promotes skeletal muscle thyroid hormone response through regulation of the MCT10 transporter
title Six1 promotes skeletal muscle thyroid hormone response through regulation of the MCT10 transporter
title_full Six1 promotes skeletal muscle thyroid hormone response through regulation of the MCT10 transporter
title_fullStr Six1 promotes skeletal muscle thyroid hormone response through regulation of the MCT10 transporter
title_full_unstemmed Six1 promotes skeletal muscle thyroid hormone response through regulation of the MCT10 transporter
title_short Six1 promotes skeletal muscle thyroid hormone response through regulation of the MCT10 transporter
title_sort six1 promotes skeletal muscle thyroid hormone response through regulation of the mct10 transporter
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607597/
https://www.ncbi.nlm.nih.gov/pubmed/34809717
http://dx.doi.org/10.1186/s13395-021-00281-6
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