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

  1. Hiroaki Eshima

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  2. Justin L Shahtout

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  3. Piyarat Siripoksup

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  4. MacKenzie J Pearson

    Sciex, Framingham, United States
    Competing interests
    MacKenzie J Pearson, is affiliated with Sciex. The author has no financial interests to declare..
  5. Ziad S Mahmassani

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  6. Patrick J Ferrara

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  7. Alexis W Lyons

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  8. John Alan Maschek

    Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  9. Alek D Peterlin

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2837-7446
  10. Anthony RP Verkerke

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  11. Jordan M Johnson

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  12. Anahy Salcedo

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  13. Jonathan J Petrocelli

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  14. Edwin R Miranda

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  15. Ethan J Anderson

    Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States
    Competing interests
    No competing interests declared.
  16. Sihem Boudina

    Department of Nutrition and Integrative Physiology, College of Health,, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  17. Qitao Ran

    Department of Cell Systems and Anatomy, The University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    No competing interests declared.
  18. James E Cox

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  19. Micah J Drummond

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  20. Katsuhiko Funai

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    For correspondence
    kfunai@utah.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3802-4756

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.

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."

Reviewing Editor

  1. Christopher Cardozo, Icahn School of Medicine at Mount Sinai, United States

Version history

  1. Preprint posted: December 20, 2021 (view preprint)
  2. Received: December 1, 2022
  3. Accepted: March 22, 2023
  4. Accepted Manuscript published: March 23, 2023 (version 1)
  5. 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.

Metrics

  • 1,413
    Page views
  • 265
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Hiroaki Eshima
  2. Justin L Shahtout
  3. Piyarat Siripoksup
  4. MacKenzie J Pearson
  5. Ziad S Mahmassani
  6. Patrick J Ferrara
  7. Alexis W Lyons
  8. John Alan Maschek
  9. Alek D Peterlin
  10. Anthony RP Verkerke
  11. Jordan M Johnson
  12. Anahy Salcedo
  13. Jonathan J Petrocelli
  14. Edwin R Miranda
  15. Ethan J Anderson
  16. Sihem Boudina
  17. Qitao Ran
  18. James E Cox
  19. Micah J Drummond
  20. Katsuhiko Funai
(2023)
Lipid hydroperoxides promote sarcopenia through carbonyl stress
eLife 12:e85289.
https://doi.org/10.7554/eLife.85289

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Haoyan Huang, Meng Qian ... Zongjin Li
    Research Article Updated

    Nitric oxide (NO), as a gaseous therapeutic agent, shows great potential for the treatment of many kinds of diseases. Although various NO delivery systems have emerged, the immunogenicity and long-term toxicity of artificial carriers hinder the potential clinical translation of these gas therapeutics. Mesenchymal stem cells (MSCs), with the capacities of self-renewal, differentiation, and low immunogenicity, have been used as living carriers. However, MSCs as gaseous signaling molecule (GSM) carriers have not been reported. In this study, human MSCs were genetically modified to produce mutant β-galactosidase (β-GALH363A). Furthermore, a new NO prodrug, 6-methyl-galactose-benzyl-oxy NONOate (MGP), was designed. MGP can enter cells and selectively trigger NO release from genetically engineered MSCs (eMSCs) in the presence of β-GALH363A. Moreover, our results revealed that eMSCs can release NO when MGP is systemically administered in a mouse model of acute kidney injury (AKI), which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs. This eMSC and NO prodrug system provides a unique and tunable platform for GSM delivery and holds promise for regenerative therapy by enhancing the therapeutic efficiency of stem cells.

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Maria Körner, Susanne R Meyer ... Alexander Buchberger
    Research Article Updated

    The ATPase p97 (also known as VCP, Cdc48) has crucial functions in a variety of important cellular processes such as protein quality control, organellar homeostasis, and DNA damage repair, and its de-regulation is linked to neuromuscular diseases and cancer. p97 is tightly controlled by numerous regulatory cofactors, but the full range and function of the p97–cofactor network is unknown. Here, we identify the hitherto uncharacterized FAM104 proteins as a conserved family of p97 interactors. The two human family members VCP nuclear cofactor family member 1 and 2 (VCF1/2) bind p97 directly via a novel, alpha-helical motif and associate with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells. VCF1/2 localize to the nucleus and promote the nuclear import of p97. Loss of VCF1/2 results in reduced nuclear p97 levels, slow growth, and hypersensitivity to chemical inhibition of p97 in the absence and presence of DNA damage, suggesting that FAM104 proteins are critical regulators of nuclear p97 functions.