Ferroptosis and its role in skeletal muscle diseases

Wang, Ying; Zhang, Zepeng; Jiao, Weikai; Wang, Yanyan; Wang, Xiuge; Zhao, Yunyun; Fan, Xuechun; Tian, Lulu; Li, Xiangyan; Mi, Jia

doi:10.3389/fmolb.2022.1051866

Cited by 22 publications

(25 citation statements)

References 279 publications

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“…79 Macrophages are also essential in iron recycling by accumulating, metabolizing, and exporting it from damaged muscle fibers; defects in these pathways can lead to ferroptosis (reviewed in Alves et al and Wang et al). [80][81][82] Similarly, nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor for cell antioxidants and critical regulator of ferroptosis, is a potential therapeutic target for SM diseases. 80,83,84 Iron homeostasis, ferroptosis, and mitochondrial dysfunction is widely studied in the context of exercised and aging SM, sarcopenia, and rhabdomyolysis; its exacerbation or potential unique role in dysferlinopathy should be vetted.…”

Section: Discussionmentioning

confidence: 99%

“…[80][81][82] Similarly, nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor for cell antioxidants and critical regulator of ferroptosis, is a potential therapeutic target for SM diseases. 80,83,84 Iron homeostasis, ferroptosis, and mitochondrial dysfunction is widely studied in the context of exercised and aging SM, sarcopenia, and rhabdomyolysis; its exacerbation or potential unique role in dysferlinopathy should be vetted. 80,81 Macrophages and other monocytes also secrete the anti-angiogenic protein thrombospondin-1 (TSP-1).…”

Section: Discussionmentioning

confidence: 99%

“…80,83,84 Iron homeostasis, ferroptosis, and mitochondrial dysfunction is widely studied in the context of exercised and aging SM, sarcopenia, and rhabdomyolysis; its exacerbation or potential unique role in dysferlinopathy should be vetted. 80,81 Macrophages and other monocytes also secrete the anti-angiogenic protein thrombospondin-1 (TSP-1). 85,86 We note that monocytes are not the only source: cultured myotubes also secrete TSP-1, and dysferlin-deficient myotubes secrete significantly more TSP-1 than WT myotubes.…”

Section: Discussionmentioning

confidence: 99%

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Relative quantification of progressive changes in healthy and dysferlin‐deficient mouse skeletal muscle proteomes

Golding,

Li,

Blank

et al. 2023

Muscle and Nerve

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Introduction/AimsIndividuals with dysferlinopathies, a group of genetic muscle diseases, experience delay in the onset of muscle weakness. The cause of this delay and subsequent muscle wasting are unknown, and there are currently no clinical interventions to limit or prevent muscle weakness. To better understand molecular drivers of dysferlinopathies, age‐dependent changes in the proteomic profile of skeletal muscle (SM) in wild‐type (WT) and dysferlin‐deficient mice were identified.MethodsQuadriceps were isolated from 6‐, 18‐, 42‐, and 77‐wk‐old C57BL/6 (WT, Dysf+/+) and BLAJ (Dysf−/−) mice (n = 3, 2 male/1 female or 1 male/2 female, 24 total). Whole‐muscle proteomes were characterized using liquid chromatography‐mass spectrometry with relative quantification using TMT10plex isobaric labeling. Principle component analysis was utilized to detect age‐dependent proteomic differences over the lifespan of, and between, WT and dysferlin‐deficient SM. The biological relevance of proteins with significant variation was established using Ingenuity Pathway Analysis.ResultsOver 3200 proteins were identified between 6‐, 18‐, 42‐, and 77‐wk‐old mice. In total, 46 proteins varied in aging WT SM (p < .01), while 365 varied in dysferlin‐deficient SM. However, 569 proteins varied between aged‐matched WT and dysferlin‐deficient SM. Proteins with significant variation in expression across all comparisons followed distinct temporal trends.DiscussionProteins involved in sarcolemma repair and regeneration underwent significant changes in SM over the lifespan of WT mice, while those associated with immune infiltration and inflammation were overly represented over the lifespan of dysferlin‐deficient mice. The proteins identified herein are likely to contribute to our overall understanding of SM aging and dysferlinopathy disease progression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Relative quantification of progressive changes in healthy and dysferlin‐deficient mouse skeletal muscle proteomes

Golding,

Li,

Blank

et al. 2023

Muscle and Nerve

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“…However, inhibition of ferroptosis alone enhanced cell viability following palmitate exposure while inhibition of apoptosis alone did not, possibly revealing a greater importance of ferroptosis. The role of ferroptosis in skeletal muscle pathologies is just emerging but has been implicated in the development of sarcopenia, rhabdomyolysis and inflammatory myopathies(41). Our study also implicates skeletal muscle ferroptosis in sarcopenic obesity.…”

Section: Discussionmentioning

confidence: 99%

Class IIa HDACs inhibit cell death pathways and protect muscle integrity in response to lipotoxicity

Martin

Connor

Sanigorski

et al. 2022

Preprint

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Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle. This metabolic reprogramming was linked with reduced expression of p53-dependent genes that mediate apoptosis and ferroptosis, which preserved cell viability in response to lipotoxicity. Mechanistically, impaired mitochondrial metabolism reduced acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis, while redox drivers of ferroptosis were also reduced. Overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice enhanced oxidative capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of the oxidative state of skeletal muscle, and that this metabolic reprogramming, considered deleterious for normal metabolism, is critical to preserve muscle integrity in response to lipotoxicity.

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“…Protein arginine methylation is a widely occurring and relatively conserved protein post-translational modification in eukaryotes that is involved in a variety of biological processes, including RNA processing, DNA repair, chromosome organization, protein folding, and gene expression. − These modifications are primarily catalyzed by nine members of the protein arginine methyltransferases (PRMTs) that transfer the methyl groups from S -adenosyl- l -methionine (SAM) to the guanidinium group of arginine. Monomethylated arginine is formed as a first step and serves as an intermediate, followed by asymmetrical and symmetrical dimethylation.…”

Section: Introductionmentioning

confidence: 99%

mNeuCode Empowers Targeted Proteome Analysis of Arginine Dimethylation

Wang

Yan

et al. 2023

Anal. Chem.

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Characterization of protein arginine dimethylation presents significant challenges due to its occurrence at the substoichiometric level. To enable a targeted MS/MS analysis of these dimethylation sites, we developed the mNeuCode (methyl-neutron-coding) tag by metabolically labeling methylarginine with stable isotopes during cell culture, which generated a diagnostic peak containing the NeuCode isotopologue signature in a high-resolution MS scan. A software tool, termed NeuCodeFinder, was developed for screening the NeuCode signatures in mass spectra. Therefore, a targeted MS/MS workflow was established for proteome-wide discovery of arginine dimethylation. The efficacy and utility were demonstrated by identifying 176 arginine dimethylation sites residing on 70 proteins in HeLa cells. Among them, 38% of the sites and 29% of the dimethylated proteins are novel, including five novel arginine dimethylation sites on the protein FAM98A, which is a substrate of protein arginine methyltransferase 1 (PRMT1). Our results show that deletion of FAM98A in HeLa cells suppressed cell migration, and importantly, dimethylation-deficient mutation suppressed this process as well. Therefore, the PRMT1-FAM98A pathway mediates cell migration possibly through dimethylation of these newly identified sites of FAM98A. Our study might drive the methodological shift from shotgun-based to targeted proteome analysis for interrogation of the substoichiometric biomolecules by using NeuCode-enabled techniques.

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Ferroptosis and its role in skeletal muscle diseases

Cited by 22 publications

References 279 publications

Relative quantification of progressive changes in healthy and dysferlin‐deficient mouse skeletal muscle proteomes

Relative quantification of progressive changes in healthy and dysferlin‐deficient mouse skeletal muscle proteomes

Class IIa HDACs inhibit cell death pathways and protect muscle integrity in response to lipotoxicity

mNeuCode Empowers Targeted Proteome Analysis of Arginine Dimethylation

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