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TNF-α upregulates macroautophagic processing of APP/β-amyloid in a human rhabdomyosarcoma cell line
Christian W Keller1, Matthias Schmitz, Christian Münz
1Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
Abstract:
Sporadic inclusion body myositis is a chronic progressive, inflammatory disorder of the skeletal muscle. No effective treatment is available for this debilitating condition and the complex disease pathology is far from being understood. The major hallmark of the pathomechanisms is the co-occurrence of inflammatory as well as degenerative cascades including aggregates consisting of β-amyloid within skeletal muscle fibers. Macroautophagy, a homeostatic process that shuttles cytoplasmic constituents into endosomal and lysosomal compartments, has recently been shown to be upregulated via the proinflammatory cytokine TNF-α in human skeletal muscle cells. In a human cell line from rhabdomyosarcoma as a model to study muscle cells, we here show that TNF-α-mediated upregulation of macroautophagy modulates APP and β-amyloid load and can be blocked by inhibition of macroautophagy. Thus, macroautophagy may be a crucial mediator between inflammation and β-amyloid-associated degeneration in skeletal muscle.
Insights
Inclusion body myositis involves inflammation and degeneration. Macroautophagy, triggered by TNF-α, impacts amyloid pathology and may be a therapeutic target for this muscle disorder.
Area of Science:
- Muscle biology
- Neuroimmunology
- Cellular pathology
Background:
- Sporadic inclusion body myositis (IBM) is a progressive inflammatory muscle disease with no effective treatments.
- IBM pathology involves both inflammation and degeneration, including beta-amyloid aggregates in muscle fibers.
- Macroautophagy, a cellular degradation process, is upregulated by the inflammatory cytokine TNF-α in muscle cells.
Purpose of the Study:
- To investigate the role of macroautophagy in TNF-α-mediated pathology in a muscle cell model.
- To determine if macroautophagy influences amyloid precursor protein (APP) and beta-amyloid (Aβ) levels in muscle cells.
- To assess the potential of inhibiting macroautophagy as a therapeutic strategy for IBM.
Main Methods:
- Utilized a human rhabdomyosarcoma cell line as a model for muscle cells.
- Administered tumor necrosis factor-alpha (TNF-α) to induce macroautophagy.
- Assessed the effects of TNF-α and macroautophagy inhibition on APP and Aβ load.
Main Results:
- TNF-α upregulated macroautophagy in the muscle cell model.
- This TNF-α-mediated macroautophagy modulated APP and Aβ levels.
- Inhibiting macroautophagy blocked these modulations, suggesting a direct link.
Conclusions:
- Macroautophagy is upregulated by TNF-α in muscle cells, influencing amyloid pathology.
- Macroautophagy may act as a key mediator connecting inflammation and beta-amyloid degeneration in IBM.
- Targeting macroautophagy presents a potential therapeutic avenue for sporadic inclusion body myositis.
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