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The skeletal muscle circadian clock regulates titin splicing through RBM20

Circadian rhythms are maintained by a cell-autonomous, transcriptional–translational feedback loop known as the molecular clock. While previous research suggests a role of the molecular clock in regulating skeletal muscle structure and function, no mechanisms have connected the molecular clock to sa...

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Autores principales: Riley, Lance A, Zhang, Xiping, Douglas, Collin M, Mijares, Joseph M, Hammers, David W, Wolff, Christopher A, Wood, Neil B, Olafson, Hailey R, Du, Ping, Labeit, Siegfried, Previs, Michael J, Wang, Eric T, Esser, Karyn A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9473687/
https://www.ncbi.nlm.nih.gov/pubmed/36047761
http://dx.doi.org/10.7554/eLife.76478
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author Riley, Lance A
Zhang, Xiping
Douglas, Collin M
Mijares, Joseph M
Hammers, David W
Wolff, Christopher A
Wood, Neil B
Olafson, Hailey R
Du, Ping
Labeit, Siegfried
Previs, Michael J
Wang, Eric T
Esser, Karyn A
author_facet Riley, Lance A
Zhang, Xiping
Douglas, Collin M
Mijares, Joseph M
Hammers, David W
Wolff, Christopher A
Wood, Neil B
Olafson, Hailey R
Du, Ping
Labeit, Siegfried
Previs, Michael J
Wang, Eric T
Esser, Karyn A
author_sort Riley, Lance A
collection PubMed
description Circadian rhythms are maintained by a cell-autonomous, transcriptional–translational feedback loop known as the molecular clock. While previous research suggests a role of the molecular clock in regulating skeletal muscle structure and function, no mechanisms have connected the molecular clock to sarcomere filaments. Utilizing inducible, skeletal muscle specific, Bmal1 knockout (iMSBmal1(-/-)) mice, we showed that knocking out skeletal muscle clock function alters titin isoform expression using RNAseq, liquid chromatography–mass spectrometry, and sodium dodecyl sulfate-vertical agarose gel electrophoresis. This alteration in titin’s spring length resulted in sarcomere length heterogeneity. We demonstrate the direct link between altered titin splicing and sarcomere length in vitro using U7 snRNPs that truncate the region of titin altered in iMSBmal1(-/-) muscle. We identified a mechanism whereby the skeletal muscle clock regulates titin isoform expression through transcriptional regulation of Rbm20, a potent splicing regulator of titin. Lastly, we used an environmental model of circadian rhythm disruption and identified significant downregulation of Rbm20 expression. Our findings demonstrate the importance of the skeletal muscle circadian clock in maintaining titin isoform through regulation of RBM20 expression. Because circadian rhythm disruption is a feature of many chronic diseases, our results highlight a novel pathway that could be targeted to maintain skeletal muscle structure and function in a range of pathologies.
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spelling pubmed-94736872022-09-15 The skeletal muscle circadian clock regulates titin splicing through RBM20 Riley, Lance A Zhang, Xiping Douglas, Collin M Mijares, Joseph M Hammers, David W Wolff, Christopher A Wood, Neil B Olafson, Hailey R Du, Ping Labeit, Siegfried Previs, Michael J Wang, Eric T Esser, Karyn A eLife Cell Biology Circadian rhythms are maintained by a cell-autonomous, transcriptional–translational feedback loop known as the molecular clock. While previous research suggests a role of the molecular clock in regulating skeletal muscle structure and function, no mechanisms have connected the molecular clock to sarcomere filaments. Utilizing inducible, skeletal muscle specific, Bmal1 knockout (iMSBmal1(-/-)) mice, we showed that knocking out skeletal muscle clock function alters titin isoform expression using RNAseq, liquid chromatography–mass spectrometry, and sodium dodecyl sulfate-vertical agarose gel electrophoresis. This alteration in titin’s spring length resulted in sarcomere length heterogeneity. We demonstrate the direct link between altered titin splicing and sarcomere length in vitro using U7 snRNPs that truncate the region of titin altered in iMSBmal1(-/-) muscle. We identified a mechanism whereby the skeletal muscle clock regulates titin isoform expression through transcriptional regulation of Rbm20, a potent splicing regulator of titin. Lastly, we used an environmental model of circadian rhythm disruption and identified significant downregulation of Rbm20 expression. Our findings demonstrate the importance of the skeletal muscle circadian clock in maintaining titin isoform through regulation of RBM20 expression. Because circadian rhythm disruption is a feature of many chronic diseases, our results highlight a novel pathway that could be targeted to maintain skeletal muscle structure and function in a range of pathologies. eLife Sciences Publications, Ltd 2022-09-01 /pmc/articles/PMC9473687/ /pubmed/36047761 http://dx.doi.org/10.7554/eLife.76478 Text en © 2022, Riley et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Riley, Lance A
Zhang, Xiping
Douglas, Collin M
Mijares, Joseph M
Hammers, David W
Wolff, Christopher A
Wood, Neil B
Olafson, Hailey R
Du, Ping
Labeit, Siegfried
Previs, Michael J
Wang, Eric T
Esser, Karyn A
The skeletal muscle circadian clock regulates titin splicing through RBM20
title The skeletal muscle circadian clock regulates titin splicing through RBM20
title_full The skeletal muscle circadian clock regulates titin splicing through RBM20
title_fullStr The skeletal muscle circadian clock regulates titin splicing through RBM20
title_full_unstemmed The skeletal muscle circadian clock regulates titin splicing through RBM20
title_short The skeletal muscle circadian clock regulates titin splicing through RBM20
title_sort skeletal muscle circadian clock regulates titin splicing through rbm20
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9473687/
https://www.ncbi.nlm.nih.gov/pubmed/36047761
http://dx.doi.org/10.7554/eLife.76478
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