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Cited by 63Muscle Physiology and DisordersNutrition and Health in AgingExercise and Physiological Responses

The DOI matches its Crossref record; 207 of the 207 references it cites were found in a registry or an index.

Reactive oxygen species in the pathogenesis of sarcopenia

Open access
Xu, Hongyang, Brown, Jacob L., Bhaskaran, Shylesh, Van Remmen, Holly·2025·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2024.11.046PMC PMC11816180
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Abstract

One of the most critical factors impacting healthspan in the elderly is the loss of muscle mass and function, clinically referred to as sarcopenia. Muscle atrophy and weakness lead to loss of mobility, increased risk of injury, metabolic changes and loss of independence. Thus, defining the underlying mechanisms of sarcopenia is imperative to enable the development of effective interventions to preserve muscle function and quality in the elderly and improve healthspan. Over the past few decades, understanding the roles of mitochondrial dysfunction and oxidative stress has been a major focus of studies seeking to reveal critical molecular pathways impacted during aging. In this review, we will highlight how oxidative stress might contribute to sarcopenia by discussing the impact of oxidative stress on the loss of innervation and alteration in the neuromuscular junction (NMJ), on muscle mitochondrial function and atrophy pathways, and finally on muscle contractile function.

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Crossref · 10.1016/j.freeradbiomed.2024.11.046

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Figures

Fig. 1. Summary of tissue specific antioxidant models. The table above illustrates the genetic mouse models used to investigate the impact of neuronal versus muscle oxidative stress on muscle atrophy and weakness. Deleting key antioxidant enzymes specifically in skeletal muscle results in muscle weakness and degeneration of the NMJ. Similarly, when these enzymes are deleted in neurons, we observe muscle atrophy, weakness, and NMJ degeneration. These findings suggest that the sarcopenia phenotype is triggered by peroxides originating from both muscle and motor neurons. Created in BioRender. Van Remmen, H. (2024) https://BioRender.com/n40q480.
Fig. 1. Summary of tissue specific antioxidant models. The table above illustrates the genetic mouse models used to investigate the impact of neuronal versus muscle oxidative stress on muscle atrophy and weakness. Deleting key antioxidant enzymes specifically in skeletal muscle results in muscle weakness and degeneration of the NMJ. Similarly, when these enzymes are deleted in neurons, we observe muscle atrophy, weakness, and NMJ degeneration. These findings suggest that the sarcopenia phenotype is triggered by peroxides originating from both muscle and motor neurons. Created in BioRender. Van Remmen, H. (2024) https://BioRender.com/n40q480.CC BY-NC-ND · PubMed Central
Fig. 2. Impact of hydroperoxides on sarcopenia. Schematic showing that aging increases mitochondrial hydroperoxide generation. Studies from our laboratory and others have shown that mitochondrial hydroperoxide generation can lead to NMJ degeneration and denervation. Denervation often occurs before other hallmarks of sarcopenia such as muscle loss and dysfunction. Studies from our laboratory show that mitochondrial lipid hydroperoxide generation is elevated in denervated muscle, which leads to increased muscle protein breakdown. In addition, electron transport chain ROS is also associated with increased muscle protein breakdown. These data from multiple laboratories suggest that hydroperoxides may be a causal agent of sarcopenia.
Fig. 2. Impact of hydroperoxides on sarcopenia. Schematic showing that aging increases mitochondrial hydroperoxide generation. Studies from our laboratory and others have shown that mitochondrial hydroperoxide generation can lead to NMJ degeneration and denervation. Denervation often occurs before other hallmarks of sarcopenia such as muscle loss and dysfunction. Studies from our laboratory show that mitochondrial lipid hydroperoxide generation is elevated in denervated muscle, which leads to increased muscle protein breakdown. In addition, electron transport chain ROS is also associated with increased muscle protein breakdown. These data from multiple laboratories suggest that hydroperoxides may be a causal agent of sarcopenia.CC BY-NC-ND · PubMed Central
Fig. 3. Impact of oxidative stress on muscle contractile function. Skeletal muscle produces force through excitation-contraction coupling (E-C coupling), which involves the membrane excitability and sensing of an action potential of the sarcolemma, and the release and regulation of Ca2+ ions from and back to sarcoplasmic reticulum (SR), and finally the relative interactions between contractile filaments to output force production. With elevated oxidative stress, deleterious oxidative modifications can occur on one or multiple sites within the E-C coupling system, which might lead to the impaired muscle force generation.
Fig. 3. Impact of oxidative stress on muscle contractile function. Skeletal muscle produces force through excitation-contraction coupling (E-C coupling), which involves the membrane excitability and sensing of an action potential of the sarcolemma, and the release and regulation of Ca2+ ions from and back to sarcoplasmic reticulum (SR), and finally the relative interactions between contractile filaments to output force production. With elevated oxidative stress, deleterious oxidative modifications can occur on one or multiple sites within the E-C coupling system, which might lead to the impaired muscle force generation.CC BY-NC-ND · PubMed Central

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Items 201–207 of 207

Research works printed but not linked: 2

  1. Xu, 2021, Muscle mitochondrial catalase expression prevents neuromuscular junction disruption, atrophy, and weakness in a mouse model of accelerated sarcopenia, J. Cachexia Sarcopenia Muscle., 12, 1582, 10.1002/jcsm.12768 · DOI
  2. McClung, 2009, Calpain-1 is required for hydrogen peroxide-induced myotube atrophy, Am. J. Physiol. Cell Physiol., 296, C363, 10.1152/ajpcell.00497.2008 · DOI

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Metadata

Authors
Xu, H., Brown, J. L., Bhaskaran, S., & Van Remmen, H.
Affiliations
Oklahoma Medical Research Foundation (US)
ORCID
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2025-02
Volume
227
Pages
446-458
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2024.11.046
PMC
PMC11816180
OpenAlex
W4404813617
Cited by
61
References
206
Citations by year
2026: 34 · 2025: 27
FWCI
2.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
Funders
  • National Institute on Aging
  • US Department of Veterans Affairs
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
  • Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
Keywords
sarcopenia, reactive oxygen species, oxidative stress, muscle atrophy, muscle weakness, mitochondrial dysfunction, neuromuscular junction, aging, healthspan, muscle contractility, older adults
MeSH terms
Aging, Animals, Humans, Mitochondria, Mitochondria, Muscle, Muscle Contraction, Muscular Atrophy, Neuromuscular Junction, Reactive Oxygen Species, Oxidative Stress, Muscle, Skeletal, Sarcopenia

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