The skeletal muscle circadian clock regulates titin splicing through RBM20

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Abstract

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, LC-MS, and SDS-VAGE. 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 down-regulation 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.

Data availability

Sequencing data have been deposited in GEO under accession code: GSE189865

The following data sets were generated

1. Riley LA
2. Esser KA
(2021) The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing
NCBI Gene Exression Omnibus, GSE189865.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE189865

Article and author information

Author details

Lance A Riley

Department of Physiology and Functional Genomics, University of Florida, Gainsville, United States

Competing interests
The authors declare that no competing interests exist.
Xiping Zhang

Department of Physiology and Functional Genomics, University of Florida, Gainesville, United States

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The authors declare that no competing interests exist.
Collin M Douglas

Department of Physiology and Functional Genomics, University of Florida, Gainesville, United States

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The authors declare that no competing interests exist.
Joseph M Mijares

Department of Physiology and Functional Genomics, University of Florida, Gainsville, United States

Competing interests
The authors declare that no competing interests exist.
David W Hammers

Department of Pharmacology and Therapeutics, University of Florida, Gainesville, United States

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2129-4047
Christopher A Wolff

Department of Physiology and Functional Genomics, University of Florida, Gainesville, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5129-5692
Neil B Wood

Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, United States

Competing interests
The authors declare that no competing interests exist.
Hailey R Olafson

Department of Molecular Genetics of Microbiology, University of Florida, Gainesville, United States

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The authors declare that no competing interests exist.
Ping Du

Department of Physiology and Functional Genomics, University of Florida, Gainesville, United States

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The authors declare that no competing interests exist.
Siegfried Labeit

Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

Competing interests
The authors declare that no competing interests exist.
Michael J Previs

Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, United States

Competing interests
The authors declare that no competing interests exist.
Eric T Wang

Department of Molecular Genetics of Microbiology, University of Florida, Gainesville, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2655-5525
Karyn A Esser

Department of Physiology and Functional Genomics, University of Florida, Gainesville, United States

For correspondence
kaesser@ufl.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5791-1441

Funding

NIH Office of the Director (DP5OD017865)

Eric T Wang

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR066082,F31AR070625)

Karyn A Esser

National Heart Lung and Blood Institute (R01HL157487)

Michael J Previs

Fondation Leducq (13CVD04)

David W Hammers
Siegfried Labeit

The authors declare that the funders had no impact on the design or data collection or writing of this manuscript

Ethics

Animal experimentation: All experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved and monitored by the University of Florida Institutional Animal Care and Use Committee Protocols (IACUC numbers: 201809136, IACUC202100000018).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.