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other·preclinical research, biomedical research, geriatrics, nutrition, antioxidants·PMC10076018

Lipid hydroperoxides promote sarcopenia through carbonyl stress

eLife · 21 authors, 15 centres

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TL;DR

This study shows that lipid hydroperoxides increase with age and disuse in skeletal muscle, and that their accumulation is sufficient to cause muscle atrophy. Genetic or pharmacological neutralization of these molecules prevented muscle atrophy and weakness in mice.

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570 CHARS

Using mouse models and C2C12 myotubes, researchers found that LOOH accumulate with aging and disuse (hindlimb unloading) and that this accumulation is sufficient to promote atrophy. Genetic deletion of GPx4 (increasing LOOH) augmented atrophy, while deletion of LPCAT3 (reducing LOOH formation) or pharmacological neutralization with L-carnosine or N-acetylcarnosine prevented atrophy and weakness. The findings suggest LOOH-derived carbonyl stress is a key mediator of muscle dysfunction. Implications point to LOOH and carbonyl stress as potential therapeutic targets.

STUDY TYPE

other

SPECIALTY

preclinical research

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100% · A

ORIGINAL PAPER

PMC10076018

Lipid hydroperoxides promote sarcopenia through carbonyl stress

eLife

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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 pharmacological 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 pharmacological suppression.

CITATION EXPORT

Hiroaki Eshima, Justin L Shahtout, Piyarat Siripoksup et al.. Lipid hydroperoxides promote sarcopenia through carbonyl stress. eLife. (2023). https://doi.org/10.7554/eLife.85289

AUTHORS

21 · 15 CENTRES

Hiroaki Eshima, Justin L Shahtout, Piyarat Siripoksup, MacKenzie J Pearson, Ziad S Mahmassani, Patrick J Ferrara, Alexis W Lyons, John Alan Maschek, Alek D Peterlin, Anthony RP Verkerke, Jordan M Johnson, Anahy Salcedo, Jonathan J Petrocelli, Edwin R Miranda, Ethan J Anderson, Sihem Boudina, Qitao Ran, James E Cox, Micah J Drummond, Katsuhiko Funai, Christopher Cardozo

1 https://ror.org/03r0ha626Diabetes and Metabolism Research Center, University of Utah Salt Lake City United States
2 https://ror.org/03r0ha626Molecular Medicine Program, University of Utah Salt Lake City United States
3 https://ror.org/01tqqny90Department of International Tourism, Nagasaki International University Nagasaki Japan
4 https://ror.org/03r0ha626Department of Physical Therapy & Athletic Training, University of Utah Salt Lake City United States
5 https://ror.org/037mh3841Sciex Framingham United States
6 https://ror.org/03r0ha626Department of Nutrition & Integrative Physiology, University of Utah Salt Lake City United States
7 https://ror.org/03r0ha626Metabolomics Core Research Facility, University of Utah Salt Lake City United States
8 https://ror.org/036jqmy94Fraternal Order of Eagles Diabetes Research Center, University of Iowa Iowa City United States
9 https://ror.org/02f6dcw23Department of Cell Systems and Anatomy, The University of Texas Health Science Center at San Antonio San Antonio United States
10 https://ror.org/03r0ha626Department of Biochemistry, University of Utah Salt Lake City United States
https://ror.org/04a9tmd77Icahn School of Medicine at Mount Sinai United States
https://ror.org/012mef835Augusta University United States
https://ror.org/04a9tmd77Icahn School of Medicine at Mount Sinai United States
https://ror.org/04a9tmd77Icahn School of Medicine at Mount Sinai United States
https://ror.org/04a9tmd77Icahn School of Medicine at Mount Sinai United States

EDITOR / REVIEWER

Christopher Cardozo, Carlos Isales, Christopher Cardozo, Christopher Cardozo