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

Zhang, Lijiao; Li, Danyang; Chang, Chun; Sun, Yongchang

doi:10.2147/copd.s377226

Cited by 10 publications

(7 citation statements)

References 37 publications

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“…For example, several studies have found an increased lipofuscin accumulation in COPD quadriceps [ 126 ] and higher levels of hydroxy-2-nonenal (4-HNE) in quadriceps tissue [ 87 , 127 ], as well as in cultured myotubes from COPD patients [ 128 ]. 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 ]. Finally, nitrosative stress is also increased, as evidenced by higher tyrosine nitration levels in the quadriceps from COPD patients compared to those from healthy subjects [ 122 ], as well as inducible nitric oxide synthase and 3-nitrotyrosine levels [ 127 ].…”

Section: Oxidative and Nitrosative Stressmentioning

confidence: 99%

Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting

Henrot

Dupin

Schilfarth

et al. 2023

IJMS

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Chronic obstructive pulmonary disease (COPD) is a worldwide prevalent respiratory disease mainly caused by tobacco smoke exposure. COPD is now considered as a systemic disease with several comorbidities. Among them, skeletal muscle dysfunction affects around 20% of COPD patients and is associated with higher morbidity and mortality. Although the histological alterations are well characterized, including myofiber atrophy, a decreased proportion of slow-twitch myofibers, and a decreased capillarization and oxidative phosphorylation capacity, the molecular basis for muscle atrophy is complex and remains partly unknown. Major difficulties lie in patient heterogeneity, accessing patients’ samples, and complex multifactorial process including extrinsic mechanisms, such as tobacco smoke or disuse, and intrinsic mechanisms, such as oxidative stress, hypoxia, or systemic inflammation. Muscle wasting is also a highly dynamic process whose investigation is hampered by the differential protein regulation according to the stage of atrophy. In this review, we report and discuss recent data regarding the molecular alterations in COPD leading to impaired muscle mass, including inflammation, hypoxia and hypercapnia, mitochondrial dysfunction, diverse metabolic changes such as oxidative and nitrosative stress and genetic and epigenetic modifications, all leading to an impaired anabolic/catabolic balance in the myocyte. We recapitulate data concerning skeletal muscle dysfunction obtained in the different rodent models of COPD. Finally, we propose several pathways that should be investigated in COPD skeletal muscle dysfunction in the future.

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Section: Oxidative and Nitrosative Stressmentioning

confidence: 99%

Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting

Henrot

Dupin

Schilfarth

et al. 2023

IJMS

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“…However, iron supplements, nutritional supplements or iron-rich diets should be utilized with caution because they are likely to be detrimental, as iron may increase ROS and ferroptosis. In particular, ferroptosis has been demonstrated to be involved in the pathogenesis of COPD-related skeletal muscle dysfunction (69). Iron levels of COPD patients should be determined, and according to their levels, patients should be supplemented with iron as appropriate.…”

Section: Discussionmentioning

confidence: 99%

Heme oxygenase-1 determines the cell fate of ferroptotic death of alveolar macrophages in COPD

Yang

Guo

et al. 2023

Front. Immunol.

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BackgroundDespite an increasing understanding of chronic obstructive pulmonary disease (COPD) pathogenesis, the mechanisms of diverse cell populations in the human lung remain unknown. Using single-cell RNA sequencing (scRNA-Seq), we can reveal changes within individual cell populations in COPD that are important for disease pathogenesis and characteristics. MethodsWe performed scRNA-Seq on lung tissue obtained from donors with non-COPD and mild-to-moderate COPD to identify disease-related genes within different cell types. We testified the findings using qRT−PCR, immunohistochemistry, immunofluorescence and Western blotting from 25 additional subjects and RAW 264.7 macrophages. Targeting ferroptosis with the ferroptosis inhibitor ferrostatin-1, iron chelator deferoxamine or HO-1 inhibitor zinc protoporphyrin was administered in the experimental cigarette smoke COPD mouse model.ResultsWe identified two populations of alveolar macrophages (AMs) in the human lung that were dysregulated in COPD patients. We discovered that M2-like AMs modulate susceptibility to ferroptosis by disrupting lipid and iron homeostasis both in vivo and in vitro. The discrepancy in sensitivity to ferroptosis can be determined and regulated by HO-1. In contrast, M1-like AMs showed the ability to attenuate oxidative stress and exert resistance to ferroptosis. In addition, the expression of genes within M2-like AMs is also involved in defects in phagocytosis and lysosome distortion. This ferroptotic phenotype was ameliorated by antiferroptotic compounds, iron chelators and HO-1 inhibitors. During COPD, the accumulation of lipid peroxidation drives ferroptosis-sensitive M2-like AMs, while M1-like AMs show characteristics of ferroptosis resistance. Ferroptotic M2 AMs lose their anti-inflammatory and repair functions but provoke inflammatory responses, resulting in consistent inflammation and tissue damage in the presence of M1 AMs in COPD. ConclusionAppropriate interventions in ferroptosis can reduce the occurrence of infections and acute onset, and delay the COPD process.

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“…In retinal pigment epithelium cells, stabilized by the 3%O 2 hypoxia condition and PHD inhibitor dimethyloxalylglycine (DMOG) treatment, HIF aggravates sodium iodate-induced ferroptosis by upregulating superoxide dismutase ( SOD ) to execute a peroxidative rather than antioxidative role, as well as increasing the iron importers ZIP8 and ZIP14 to enhance iron import [ 132 ]. Moreover, HIF-2α was found to be upregulated by myostatin in response to cigarette smoke exposure, leading to ferroptosis in myotubes and chronic obstructive pulmonary disease-related skeletal muscle dysfunction [ 133 ].…”

Section: The Mechanism and Regulation Of Ferroptosis Modulated By Hyp...mentioning

confidence: 99%

Ferroptosis Regulated by Hypoxia in Cells

Zheng

Liang

Zhang

2023

Cells

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Ferroptosis is an oxidative damage-related, iron-dependent regulated cell death with intracellular lipid peroxide accumulation, which is associated with many physiological and pathological processes. It exhibits unique features that are morphologically, biochemically, and immunologically distinct from other regulated cell death forms. Ferroptosis is regulated by iron metabolism, lipid metabolism, anti-oxidant defense systems, as well as various signal pathways. Hypoxia, which is found in a group of physiological and pathological conditions, can affect multiple cellular functions by activation of the hypoxia-inducible factor (HIF) signaling and other mechanisms. Emerging evidence demonstrated that hypoxia regulates ferroptosis in certain cell types and conditions. In this review, we summarize the basic mechanisms and regulations of ferroptosis and hypoxia, as well as the regulation of ferroptosis by hypoxia in physiological and pathological conditions, which may contribute to the numerous diseases therapies.

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

Cited by 10 publications

References 37 publications

Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting

Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting

Heme oxygenase-1 determines the cell fate of ferroptotic death of alveolar macrophages in COPD

Ferroptosis Regulated by Hypoxia in Cells

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