Extensive alternative splicing transitions during postnatal skeletal muscle development are required for Ca2+ handling

Abstract

Postnatal development of skeletal muscle is a highly dynamic period of tissue remodeling. Here we used RNA-seq to identify transcriptome changes from late embryonic to adult mouse muscle and demonstrate that alternative splicing developmental transitions impact muscle physiology. The first two weeks after birth are particularly dynamic for differential gene expression and alternative splicing transitions, and calcium-handling functions are significantly enriched among genes that undergo alternative splicing. We focused on the postnatal splicing transitions of the three calcineurin A genes, calcium-dependent phosphatases that regulate multiple aspects of muscle biology. Redirected splicing of calcineurin A to the fetal isoforms in adult muscle and in differentiated C2C12 slows the timing of muscle relaxation, promotes nuclear localization of calcineurin target Nfatc3, and/or affects expression of Nfatc transcription targets. The results demonstrate a previously unknown specificity of calcineurin isoforms as well as the broader impact of alternative splicing during muscle postnatal development.

Article and author information

Author details

  1. Amy Elizabeth Brinegar

    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Zheng Xia

    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. James Anthony Loehr

    Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Wei Li

    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. George Gerald Rodney

    Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Thomas A Cooper

    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
    For correspondence
    tcooper@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9238-0578

Funding

National Institutes of Health (R01AR045653)

  • Thomas A Cooper

Muscular Dystrophy Association (RG4205)

  • Thomas A Cooper

National Institutes of Health (R01HL045565)

  • Thomas A Cooper

National Institutes of Health (R01AR060733)

  • Thomas A Cooper

National Institutes of Health (T32 HL007676)

  • James Anthony Loehr

National Institutes of Health (R01HG007538)

  • Wei Li

National Institutes of Health (R01CA193466)

  • Wei Li

National Institutes of Health (R01AR061370)

  • George Gerald Rodney

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Benjamin J Blencowe, University of Toronto, Canada

Ethics

Animal experimentation: All animals were handled following the NIH Guidelines for Use and Care of Laboratory Animals that were approved by the Institutional Animal Care and Use Committee (IACUC) at Baylor College of Medicine, protocol AN-1682).

Version history

  1. Received: March 29, 2017
  2. Accepted: August 4, 2017
  3. Accepted Manuscript published: August 11, 2017 (version 1)
  4. Version of Record published: August 22, 2017 (version 2)
  5. Version of Record updated: January 2, 2018 (version 3)

Copyright

© 2017, Brinegar 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. Amy Elizabeth Brinegar
  2. Zheng Xia
  3. James Anthony Loehr
  4. Wei Li
  5. George Gerald Rodney
  6. Thomas A Cooper
(2017)
Extensive alternative splicing transitions during postnatal skeletal muscle development are required for Ca2+ handling
eLife 6:e27192.
https://doi.org/10.7554/eLife.27192

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https://doi.org/10.7554/eLife.27192

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