Myonuclear accretion is a determinant of exercise-induced remodeling in skeletal muscle

  1. Qingnian Goh
  2. Tajeong Song
  3. Michael J Petrany
  4. Alyssa AW Cramer
  5. Chengyi Sun
  6. Sakthivel Sadayappan
  7. Se-Jin Lee
  8. Douglas P Millay  Is a corresponding author
  1. Cincinnati Children's Hospital Medical Center, United States
  2. University of Cincinnati College of Medicine, United States
  3. The Jackson Laboratory, United States

Abstract

Skeletal muscle adapts to external stimuli such as increased work. Muscle progenitors (MPs) control muscle repair due to severe damage, but the role of MP fusion and associated myonuclear accretion during exercise are unclear. While we previously demonstrated that MP fusion is required for growth using a supra-physiological model (1), questions remained about the need for myonuclear accrual during muscle adaptation in a physiological setting. Here, we developed a high-intensity interval training (HIIT) protocol and assessed the importance of MP fusion. In 8 month-old mice, HIIT led to progressive myonuclear accretion throughout the protocol, and functional muscle hypertrophy. Abrogation of MP fusion at the onset of HIIT resulted in exercise intolerance and fibrosis. In contrast, ablation of MP fusion 4 weeks into HIIT, preserved exercise tolerance but attenuated hypertrophy. We conclude that myonuclear accretion is required for different facets of exercise-induced adaptive responses, impacting both muscle repair and hypertrophic growth.

Data availability

All data generated in this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Qingnian Goh

    Department of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Tajeong Song

    Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Michael J Petrany

    Depatment of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alyssa AW Cramer

    Department of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2997-5066
  5. Chengyi Sun

    Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8500-1878
  6. Sakthivel Sadayappan

    Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Se-Jin Lee

    The Jackson Laboratory, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Douglas P Millay

    Depatment of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    For correspondence
    douglas.millay@cchmc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5188-0720

Funding

National Institutes of Health (R01AR068286)

  • Douglas P Millay

Pew Charitable Trusts

  • Douglas P Millay

National Institutes of Health (R01AG059605)

  • Douglas P Millay

National Institutes of Health (R01AR060636)

  • Se-Jin Lee

National Institutes of Health (R01HL130356)

  • Sakthivel Sadayappan

National Institutes of Health (R01HL105826)

  • Sakthivel Sadayappan

National Institutes of Health (R01AR067279)

  • Sakthivel Sadayappan

National Institutes of Health (RO1/R56HL139680)

  • Sakthivel Sadayappan

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the Cincinnati Children's Hospital Medical Center.

Copyright

© 2019, Goh 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.

Metrics

  • 5,939
    views
  • 742
    downloads
  • 94
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Qingnian Goh
  2. Tajeong Song
  3. Michael J Petrany
  4. Alyssa AW Cramer
  5. Chengyi Sun
  6. Sakthivel Sadayappan
  7. Se-Jin Lee
  8. Douglas P Millay
(2019)
Myonuclear accretion is a determinant of exercise-induced remodeling in skeletal muscle
eLife 8:e44876.
https://doi.org/10.7554/eLife.44876

Share this article

https://doi.org/10.7554/eLife.44876

Further reading

    1. Developmental Biology
    Satoshi Yamashita, Shuji Ishihara, François Graner
    Research Article

    Apical constriction is a basic mechanism for epithelial morphogenesis, making columnar cells into wedge shape and bending a flat cell sheet. It has long been thought that an apically localized myosin generates a contractile force and drives the cell deformation. However, when we tested the increased apical surface contractility in a cellular Potts model simulation, the constriction increased pressure inside the cell and pushed its lateral surface outward, making the cells adopt a drop shape instead of the expected wedge shape. To keep the lateral surface straight, we considered an alternative model in which the cell shape was determined by cell membrane elasticity and endocytosis, and the increased pressure is balanced among the cells. The cellular Potts model simulation succeeded in reproducing the apical constriction, and it also suggested that a too strong apical surface tension might prevent the tissue invagination.

    1. Cancer Biology
    2. Developmental Biology
    Sara Jaber, Eliana Eldawra ... Franck Toledo
    Research Article

    Missense ‘hotspot’ mutations localized in six p53 codons account for 20% of TP53 mutations in human cancers. Hotspot p53 mutants have lost the tumor suppressive functions of the wildtype protein, but whether and how they may gain additional functions promoting tumorigenesis remain controversial. Here, we generated Trp53Y217C, a mouse model of the human hotspot mutant TP53Y220C. DNA damage responses were lost in Trp53Y217C/Y217C (Trp53YC/YC) cells, and Trp53YC/YC fibroblasts exhibited increased chromosome instability compared to Trp53-/- cells. Furthermore, Trp53YC/YC male mice died earlier than Trp53-/- males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes in Trp53YC/YC thymic cells compared to Trp53-/- cells. Surprisingly, we recovered only one Trp53YC/YC female for 22 Trp53YC/YC males at weaning, a skewed distribution explained by a high frequency of Trp53YC/YC female embryos with exencephaly and the death of most Trp53YC/YC female neonates. Strikingly, however, when we treated pregnant females with the anti-inflammatory drug supformin (LCC-12), we observed a fivefold increase in the proportion of viable Trp53YC/YC weaned females in their progeny. Together, these data suggest that the p53Y217C mutation not only abrogates wildtype p53 functions but also promotes inflammation, with oncogenic effects in males and teratogenic effects in females.