Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB
- Washington University in St. Louis, United States
- 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.
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Author details
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).
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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Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB
eLife 11:e82016.
https://doi.org/10.7554/eLife.82016
