Lipid hydroperoxides promote sarcopenia through carbonyl stress
- University of Utah, United States
- Sciex, United States
- University of Iowa, United States
- The University of Texas Health Science Center at San Antonio, United States
Abstract
Reactive oxygen species (ROS) accumulation is a cardinal feature of skeletal muscle atrophy. ROS refers to a collection of radical molecules whose cellular signals are vast, and it is unclear which downstream consequences of ROS are responsible for the loss of muscle mass and strength. Here we show that lipid hydroperoxides (LOOH) are increased with age and disuse, and the accumulation of LOOH by deletion of glutathione peroxidase 4 (GPx4) is sufficient to augment muscle atrophy. LOOH promoted atrophy in a lysosomal-dependent, proteasomal-independent manner. In young and old mice, genetic and pharmacologic neutralization of LOOH or their secondary reactive lipid aldehydes robustly prevented muscle atrophy and weakness, indicating that LOOH-derived carbonyl stress mediates age- and disuse-induced muscle dysfunction. Our findings provide novel insights for the role of LOOH in sarcopenia including a therapeutic implication by pharmacologic suppression.
Data availability
All data generated or analyzed during this study are included in the manuscript.
Article and author information
Author details
Funding
National Institutes of Health (DK107397)
- Katsuhiko Funai
National Institutes of Health (HL149870)
- Sihem Boudina
National Institutes of Health (HL139451)
- Ziad S Mahmassani
National Institutes of Health (DK130555)
- Alek D Peterlin
National Institutes of Health (AG073493)
- Jonathan J Petrocelli
American Heart Association (915674)
- Piyarat Siripoksup
American Heart Association (18PRE33960491)
- Anthony RP Verkerke
American Heart Association (19PRE34380991)
- Jordan M Johnson
Larry H. & Gail Miller Family Foundation (Predoctoral fellowship)
- Patrick J Ferrara
Uehara Memorial Foundation (Postdoctoral fellowship)
- Hiroaki Eshima
National Institutes of Health (DK127979)
- Katsuhiko Funai
National Institutes of Health (GM144613)
- Katsuhiko Funai
National Institutes of Health (AG074535)
- Katsuhiko Funai
National Institutes of Health (AG063077)
- Katsuhiko Funai
National Institutes of Health (AG050781)
- Micah J Drummond
National Institutes of Health (HL122863)
- Ethan J Anderson
National Institutes of Health (AG057006)
- Ethan J Anderson
National Institutes of Health (AG064078)
- Qitao Ran
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Christopher Cardozo, Icahn School of Medicine at Mount Sinai, United States
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 (#20-07007) of the University of Utah.
Human subjects: Informed consent and consent to publish was obtained from subjects. All procedures were approved by institutional IRB at the University of Utah and conformed to the Declaration of Helsinki and Title 45, US Code of Federal Regulations, Part 46, "Protection of Human Subjects."
Version history
- Preprint posted: December 20, 2021 (view preprint)
- Received: December 1, 2022
- Accepted: March 22, 2023
- Accepted Manuscript published: March 23, 2023 (version 1)
- Version of Record published: April 5, 2023 (version 2)
Copyright
© 2023, Eshima 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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Lipid hydroperoxides promote sarcopenia through carbonyl stress
eLife 12:e85289.
https://doi.org/10.7554/eLife.85289
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