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.
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."
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
-
- 2,440
- views
-
- 417
- downloads
-
- 20
- 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)
Lipid hydroperoxides promote sarcopenia through carbonyl stress
eLife 12:e85289.
https://doi.org/10.7554/eLife.85289
Further reading
-
- Cell Biology
- Evolutionary Biology
Maintenance of rod-shape in bacterial cells depends on the actin-like protein MreB. Deletion of mreB from Pseudomonas fluorescens SBW25 results in viable spherical cells of variable volume and reduced fitness. Using a combination of time-resolved microscopy and biochemical assay of peptidoglycan synthesis, we show that reduced fitness is a consequence of perturbed cell size homeostasis that arises primarily from differential growth of daughter cells. A 1000-generation selection experiment resulted in rapid restoration of fitness with derived cells retaining spherical shape. Mutations in the peptidoglycan synthesis protein Pbp1A were identified as the main route for evolutionary rescue with genetic reconstructions demonstrating causality. Compensatory pbp1A mutations that targeted transpeptidase activity enhanced homogeneity of cell wall synthesis on lateral surfaces and restored cell size homeostasis. Mechanistic explanations require enhanced understanding of why deletion of mreB causes heterogeneity in cell wall synthesis. We conclude by presenting two testable hypotheses, one of which posits that heterogeneity stems from non-functional cell wall synthesis machinery, while the second posits that the machinery is functional, albeit stalled. Overall, our data provide support for the second hypothesis and draw attention to the importance of balance between transpeptidase and glycosyltransferase functions of peptidoglycan building enzymes for cell shape determination.
-
- Cell Biology
Polynucleotide kinase phosphatase (PNKP) has enzymatic activities as 3′-phosphatase and 5′-kinase of DNA ends to promote DNA ligation and repair. Here, we show that cyclin-dependent kinases (CDKs) regulate the phosphorylation of threonine 118 (T118) in PNKP. This phosphorylation allows recruitment to the gapped DNA structure found in single-strand DNA (ssDNA) nicks and/or gaps between Okazaki fragments (OFs) during DNA replication. T118A (alanine)-substituted PNKP-expressing cells exhibited an accumulation of ssDNA gaps in S phase and accelerated replication fork progression. Furthermore, PNKP is involved in poly (ADP-ribose) polymerase 1 (PARP1)-dependent replication gap filling as part of a backup pathway in the absence of OFs ligation. Altogether, our data suggest that CDK-mediated PNKP phosphorylation at T118 is important for its recruitment to ssDNA gaps to proceed with OFs ligation and its backup repairs via the gap-filling pathway to maintain genome stability.
