1. Cell Biology

The skeletal muscle circadian clock regulates titin splicing through RBM20

  1. Lance A Riley
  2. Xiping Zhang
  3. Collin M Douglas
  4. Joseph M Mijares
  5. David W Hammers
  6. Christopher A Wolff
  7. Neil B Wood
  8. Hailey R Olafson
  9. Ping Du
  10. Siegfried Labeit
  11. Michael J Previs
  12. Eric T Wang
  13. Karyn A Esser  Is a corresponding author
  1. University of Florida, United States
  2. University of Vermont, United States
  3. University of Heidelberg, Germany
https://doi.org/10.7554/eLife.76478
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Cite this article
  1. Lance A Riley
  2. Xiping Zhang
  3. Collin M Douglas
  4. Joseph M Mijares
  5. David W Hammers
  6. Christopher A Wolff
  7. Neil B Wood
  8. Hailey R Olafson
  9. Ping Du
  10. Siegfried Labeit
  11. Michael J Previs
  12. Eric T Wang
  13. Karyn A Esser
(2022)
The skeletal muscle circadian clock regulates titin splicing through RBM20
eLife 11:e76478.
https://doi.org/10.7554/eLife.76478
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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

Article and author information

Author details

  1. 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.

  2. Xiping Zhang

    Department of Physiology and Functional Genomics, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Collin M Douglas

    Department of Physiology and Functional Genomics, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. 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.

  5. David W Hammers

    Department of Pharmacology and Therapeutics, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2129-4047

  6. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5129-5692

  7. 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.

  8. Hailey R Olafson

    Department of Molecular Genetics of Microbiology, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Ping Du

    Department of Physiology and Functional Genomics, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Siegfried Labeit

    Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
    Competing interests
    The authors declare that no competing interests exist.

  11. 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.

  12. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2655-5525

  13. 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.
    ORCID icon "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

© 2022, Riley et al.

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.

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  1. Lance A Riley
  2. Xiping Zhang
  3. Collin M Douglas
  4. Joseph M Mijares
  5. David W Hammers
  6. Christopher A Wolff
  7. Neil B Wood
  8. Hailey R Olafson
  9. Ping Du
  10. Siegfried Labeit
  11. Michael J Previs
  12. Eric T Wang
  13. Karyn A Esser
(2022)
The skeletal muscle circadian clock regulates titin splicing through RBM20
eLife 11:e76478.
https://doi.org/10.7554/eLife.76478

Share this article

https://doi.org/10.7554/eLife.76478

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