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Visualization of MG53-mediated Cell Membrane Repair Using in vivo and in vitro Systems
Published on: June 30, 2011
Elevated labile iron contributes to membrane repair deficits in facioscapulohumeral muscular dystrophy
Adam J Bittel1, Surajit Bhattacharya1, Lulya Okubamariam1
1Center for Genetic Medicine Research, Children's National Research and Innovation Campus, Washington, DC 20012, USA.
Abstract:
Facioscapulohumeral muscular dystrophy (FSHD) is caused by expression of the transcription factor DUX4, which is associated with plasma membrane (PM) repair deficits. Here, we show that PM injury triggers a mild but significant increase in DUX4 mRNA expression in FSHD myoblasts. These cells demonstrate the dysregulation of genes critical for PM repair, which are sensitive and specific for FSHD muscle tissue, and include regulators of ferroptosis. FSHD myoblasts also present with elevated labile ferrous iron and lipid peroxidation-hallmarks of ferroptotic stress. In FSHD muscle biopsies, the expression of ferroptosis biomarkers is elevated, predictive of inflammation. and positively correlated with fatty infiltration. Increasing labile iron and lipid peroxidation worsen PM repair in FSHD myoblasts, while treatment with the iron chelator 2,2'-Bipyridyl and ferroptosis inhibitor ferrostatin-1 improves repair. These data are the first to identify signs of ferroptotic stress in human FSHD myoblasts and demonstrate the potential benefit of targeting ferroptosis in FSHD.
Insights
Facioscapulohumeral muscular dystrophy (FSHD) involves plasma membrane repair issues linked to DUX4. This study reveals ferroptosis stress in FSHD myoblasts, suggesting new therapeutic targets.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder characterized by progressive muscle weakness.
- DUX4 gene expression is the primary driver of FSHD pathology.
- Plasma membrane (PM) repair deficits are a known consequence of DUX4 expression in FSHD.
Purpose of the Study:
- To investigate the role of ferroptosis in FSHD pathophysiology.
- To determine if ferroptosis markers are present in FSHD muscle cells.
- To explore the therapeutic potential of targeting ferroptosis in FSHD.
Main Methods:
- Analysis of DUX4 mRNA expression in FSHD myoblasts following PM injury.
- Gene expression profiling to identify dysregulated genes in PM repair pathways.
- Measurement of labile ferrous iron and lipid peroxidation in FSHD myoblasts.
- Assessment of ferroptosis biomarkers in FSHD muscle biopsies.
- In vitro experiments using iron chelators and ferroptosis inhibitors.
Main Results:
- PM injury increases DUX4 mRNA expression in FSHD myoblasts.
- FSHD myoblasts exhibit dysregulated PM repair genes, including ferroptosis regulators.
- Elevated labile iron and lipid peroxidation indicate ferroptotic stress in FSHD myoblasts.
- Ferroptosis biomarkers are increased in FSHD muscle biopsies, correlating with inflammation and fatty infiltration.
- Iron chelation and ferroptosis inhibition improve PM repair in FSHD myoblasts.
Conclusions:
- This study identifies ferroptotic stress as a novel component of FSHD pathophysiology.
- Elevated iron and lipid peroxidation exacerbate PM repair defects in FSHD.
- Targeting ferroptosis pathways presents a promising therapeutic strategy for FSHD.
