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Review
. 2022 Nov 3:9:1051866.
doi: 10.3389/fmolb.2022.1051866. eCollection 2022.

Ferroptosis and its role in skeletal muscle diseases

Ying Wang  1 , Zepeng Zhang  2 , Weikai Jiao  1 , Yanyan Wang  3 , Xiuge Wang  3 , Yunyun Zhao  3 , Xuechun Fan  1 , Lulu Tian  4 , Xiangyan Li  5 , Jia Mi  3
Affiliations
Review

Ferroptosis and its role in skeletal muscle diseases

Ying Wang et al. Front Mol Biosci. .

Abstract

Ferroptosis is characterized by the accumulation of iron and lipid peroxidation products, which regulates physiological and pathological processes in numerous organs and tissues. A growing body of research suggests that ferroptosis is a key causative factor in a variety of skeletal muscle diseases, including sarcopenia, rhabdomyolysis, rhabdomyosarcoma, and exhaustive exercise-induced fatigue. However, the relationship between ferroptosis and various skeletal muscle diseases has not been investigated systematically. This review's objective is to provide a comprehensive summary of the mechanisms and signaling factors that regulate ferroptosis, including lipid peroxidation, iron/heme, amino acid metabolism, and autophagy. In addition, we tease out the role of ferroptosis in the progression of different skeletal muscle diseases and ferroptosis as a potential target for the treatment of multiple skeletal muscle diseases. This review can provide valuable reference for the research on the pathogenesis of skeletal muscle diseases, as well as for clinical prevention and treatment.

Keywords: fatigue; ferroptosis; mechanism; myositis; rhabdomyolysis; rhabdomyosarcoma; sarcopenia.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The processes of heme metabolism and mitochondrial iron metabolism are implicated in ferroptosis. In the endoplasmic reticulum, HO-1 degrades heme and releases iron ions, hence raising intracellular iron content and promoting ferroptosis. ABCB6 stimulates heme production by transferring CPgenIII from the cytosol to the mitochondrial membrane gap, a process that may play a role in ferroptosis. By exporting heme via the plasma membrane, ABCG2 and FLVCR1 contribute to the control of ferroptosis. Mfrn is capable of transporting iron through the inner membrane and into the mitochondrial matrix, hence elevating the iron concentration in mitochondria and inducing ferroptosis. FtMt may store free iron in mitochondria, hence reducing iron concentration and inhibiting ferroptosis. HO-1, heme oxygenase 1; ABCB6, ATP-binding cassette sub-family B member 6; ABCG2, ATP-binding cassette subfamily G member 2; Mfrn, mitoferrin; FtMt, mitochondrial ferritin.
FIGURE 2
FIGURE 2
Mechanisms for regulating ferroptosis. Iron in circulation binds to TFR1 and enters the endosome via endocytosis; then, steap3 converts Fe3+ to Fe2+. DMT1 transports Fe2+ into the lip in order to promote unstable iron accumulation and induce ferroptosis via the Fenton reaction. Methionine generates cysteine under the action of CBS and CSE for GSH synthesis. Inhibition of system Xc− reduced GSH synthesis and inactivated GPX4, promoting lipid peroxide accumulation and inducing ferroptosis. Under the catalysis of ACSL4, LPCAT3, and LOX, PUFA lipid peroxidation resulted in ferroptosis. By promoting iron release, the ferritin autophagy-related genes Atg5, Atg7, and NCOA4 induce ferroptosis. By influencing genes related to iron/heme metabolism and amino acid metabolism, Nrf2 plays a significant role in the regulation of ferroptosis. By inhibiting DPP4 activity and systemic SLC7A11 expression, or by activating SAT1 and GLS2, P53 can induce ferroptosis. FSP1 prevents lipid peroxidation by converting CoQ10 to CoQ10H2, thereby inhibiting ferroptosis. GCH1 blocks the chain propagation of lipid peroxidation by catalyzing GTP to generate BH4. TFR1, transferrin receptor 1; DMT1, divalent metal transporter 1; CBS, cystathionine β-synthase; CSE, cystathionine gamma-lyase; GSH, glutathione; GPX4, glutathione peroxidase 4; ACSL4, Acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; LOX, lipoxygenase; PUFA, polyunsaturated fatty acid; Atg5, autophagy-related gene 3; Atg7, autophagy-related gene 7; NCOA4, nuclear receptor coactivator 4; Nrf2, nuclear factor erythroid 2-related factor 2; DPP4, dipeptidyl-peptidase 4; SLC7A11, solute carrier family 7 member 11; SAT1, spermidine/spermine N1-acetyltransferase 1; GLS2, glutaminase 2; FSP1, ferroptosis suppressor protein 1; CoQ10, ubiquinone; CoQ10H2, ubiquinol; GCH1, GTP cyclohydrolase-1; GTP, Guanosine triphosphate; BH4, tetrahydrobioterin.
FIGURE 3
FIGURE 3
Sarcopenia caused by satellite cell and myoblast ferroptosis. Aging can result in satellite cell and myoblast ferroptosis. Sarcopenia is caused by the subsequent dysfunction of skeletal muscle regeneration. NADPH, nicotinamide adenine dinucleotide phosphate; Ptgs2, prostaglandin-endoperoxide synthase 2; 4-HNE, 4-hydroxynonenal; Slc39a14, zinc transporter Zip14; MDA, malondialdehyde; SLC7A11, solute carrier family 7 member 11; TFR1, transferrin receptor 1; GPX4, glutathione peroxidase 4; GSH, glutathione.
FIGURE 4
FIGURE 4
The role of ferroptosis in rhabdomyosarcoma. Oncogenic RAS mutants are the key mediator of RMS disease, which can block the ferroptosis of RMS cells induced by erastin and RSL3. The complex tris(5-chloro-8-quinolinolato) gallium (III) can induce ferroptosis in RMS cells by reducing GPX4 expression, thereby exerting therapeutic effects on RMS. The activation of PKC-NOX pathway can participate in the process of RMS disease by increasing the ferroptosis resistance of RMS cells. PKC, protein kinase C; NOX, NADPH oxidases; GPX4, glutathione peroxidase 4; GSH, glutathione.
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