Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB

  1. Gretchen A Meyer  Is a corresponding author
  2. Stavros Thomopoulos
  3. Yousef Abu-Amer
  4. Karen C Shen
  1. Washington University in St. Louis, United States
  2. Columbia University, United States

Abstract

The nuclear factor-κB (NFκB) pathway is a major thoroughfare for skeletal muscle atrophy and is driven by diverse stimuli. Targeted inhibition of NFκB through its canonical mediator IKKβ effectively mitigates loss of muscle mass across many conditions, from denervation to unloading to cancer. In this study, we used gain- and loss-of-function mouse models to examine the role of NFκB in muscle atrophy following rotator cuff tenotomy - a model of chronic rotator cuff tear. IKKβ was knocked down or constitutively activated in muscle-specific inducible transgenic mice to elicit a 2-fold gain or loss of NFκB signaling. Surprisingly, neither knockdown of IKKβ nor overexpression of caIKKβ significantly altered the loss of muscle mass following tenotomy. This finding was consistent across measures of morphological adaptation (fiber cross-sectional area, fiber length, fiber number), tissue pathology (fibrosis and fatty infiltration) and intracellular signaling (ubiquitin-proteasome, autophagy). Intriguingly, late-stage tenotomy-induced atrophy was exacerbated in male mice compared to female mice. This sex specificity was driven by ongoing decreases in fiber cross-sectional area, which paralleled the accumulation of large autophagic vesicles in male, but not female muscle. These findings suggest that tenotomy-induced atrophy is not dependent on NFκB and instead may be regulated by autophagy in a sex-specific manner.

Data availability

All data generated or analyzed during this study are included. Data files have been provided for all Figures.

Article and author information

Author details

  1. Gretchen A Meyer

    Program in Physical Therapy, Washington University in St. Louis, St. Louis, United States
    For correspondence
    meyerg@wustl.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9268-3993
  2. Stavros Thomopoulos

    Department of Orthopaedic Surgery, Columbia University, New York, United States
    Competing interests
    Stavros Thomopoulos, Reviewing editor, eLife.
  3. Yousef Abu-Amer

    Department of Orthopaedic Surgery, Washington University in St. Louis, St Louis, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5890-5086
  4. Karen C Shen

    Program in Physical Therapy, Washington University in St. Louis, St. Louis, United States
    Competing interests
    No competing interests declared.

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR071582)

  • Gretchen A Meyer

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR057836)

  • Gretchen A Meyer
  • Stavros Thomopoulos

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

Ethics

Animal experimentation: All animal work described was performed in accordance with the National Institutes of Health's Guide for the Use and Care of Laboratory Animals and was approved by the Animal Studies Committee of the Washington University School of Medicine (IACUC 20-0459).

Reviewing Editor

  1. Jameel Iqbal, DaVita Labs, United States

Publication history

  1. Received: July 20, 2022
  2. Preprint posted: July 27, 2022 (view preprint)
  3. Accepted: December 9, 2022
  4. Accepted Manuscript published: December 12, 2022 (version 1)
  5. Version of Record published: January 24, 2023 (version 2)

Copyright

© 2022, Meyer 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. Gretchen A Meyer
  2. Stavros Thomopoulos
  3. Yousef Abu-Amer
  4. Karen C Shen
(2022)
Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB
eLife 11:e82016.
https://doi.org/10.7554/eLife.82016

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