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Cited by 22Muscle Physiology and DisordersFerroptosis and cancer prognosisChronic Obstructive Pulmonary Disease (COPD) Research

Myostatin/HIF2α-Mediated Ferroptosis Is Involved in Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

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Zhang, Lijiao, Li, Danyang, Chang, Chun, Sun, Yongchang·2022·International Journal of Chronic Obstructive Pulmonary Disease
DOI 10.2147/copd.s377226PMC PMC9519128
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Abstract

Objective: Skeletal muscle dysfunction is an important comorbidity in patients with chronic obstructive pulmonary disease (COPD), and is associated with poor quality of life and reduced survival, but the mechanisms involved remain elusive. Ferroptosis is a newly discovered type of cell death resulting from iron‐dependent lipid peroxide accumulation. The purpose of this study was to examine whether ferroptosis is involved in COPD-associated skeletal muscle dysfunction. Methods: A mouse model of COPD was established after 24 weeks of cigarette smoke (CS) exposure, and mRNA sequencing, hematoxylin-eosin (H&E) staining, immunostaining (IF), RT-PCR, and Western blot were utilized to identify the changes in gastrocnemius muscles. In vitro, C2C12 myotubes were treated with CS extract (CSE) and evaluated for ferroptosis-related molecules. The pathways regulating ferroptosis were then explored in CSE-stimulated myotubes. Results: Compared with controls, COPD mice showed an enriched ferroptosis pathway. Gpx4 was decreased, while hypoxia-inducible factor (Hif) 2α was increased, at gene and protein levels. A reduced level of GSH, but increased cell death, Fe 2+ , lipid ROS, LPO, and 4-HNE were observed in COPD mice or in CSE-stimulated C2C12 myotubes, which could be ameliorated by ferroptosis inhibitors. The expression of myostatin (MSTN) was enhanced in COPD mice and CSE-stimulated myotubes. MSTN up-regulated HIF2α expression and led to ferroptosis in myotubes, whereas inhibition of MSTN binding to its receptor or inhibition/knockdown of HIF2α resulted in decreased cell death, and partially restored GPX4 and GSH. Conclusion: CS exposure induced ferroptosis in vivo and in vitro. Mechanistically, CS-exposure upregulated MSTN which further induced ferroptosis through HIF2α in skeletal muscles, which may contribute to muscle dysfunction through impairing metabolic capacity and decreasing muscle fiber numbers, revealing a potential novel therapeutic target for COPD-related skeletal muscle dysfunction. Keywords: chronic obstructive pulmonary disease, skeletal muscle dysfunction, ferroptosis, myostatin, hypoxia-inducible factor 2α

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  • Ferroptosis is increased both in vitro in CS-exposed C2C12 myotubes and in vivo in a mouse model of COPD.

    “Ferroptosis, a newly discovered type of cell death resulting from iron-dependent lipid peroxide accumulation, has been reported to be increased both in vitro in CS-exposed C2C12 myotubes and in vivo in a mouse model of COPD [129].”

    From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [129]

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Cited by

Sorted by citations

Authors
Zhang, L., Li, D., Chang, C., & Sun, Y.
Affiliations
Peking University Third Hospital (CN)
Corresponding author
  • Zhang, Lijiao
  • Li, Danyang
  • Chang, Chun
  • Sun, Yongchang
ORCID
Venue
International Journal of Chronic Obstructive Pulmonary Disease
Publisher
Informa UK Limited
Published
2022-09
Volume
Volume 17
Pages
2383-2399
ISSN
  • 1176-9106 (ISSN-L)
  • 1178-2005
DOI
10.2147/copd.s377226
PMC
PMC9519128
OpenAlex
W4296887805
Cited by
22
References
3
Citations by year
2026: 8 · 2025: 2 · 2024: 4 · 2023: 8
FWCI
1.14
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of COPD (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
Funders
National Natural Science Foundation of China (82090014, 82170048, 81770040)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
Keywords
chronic obstructive pulmonary disease, skeletal muscle dysfunction, ferroptosis, myostatin, HIF-2α, cigarette smoke exposure, GPX4, glutathione, lipid peroxidation, oxidative stress, myotubes, gastrocnemius, muscle atrophy
MeSH terms
Ferroptosis, Endothelial PAS Domain-Containing Protein 1, Animals, Eosine Yellowish-(YS), Hematoxylin, Iron, Lipid Peroxides, Quality of Life, RNA, Messenger, Reactive Oxygen Species, Muscle, Skeletal, Pulmonary Disease, Chronic Obstructive, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Myostatin

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