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Updated: Oct 7, 2025
Immunolabelling Myofiber Degeneration in Muscle Biopsies
Published on: December 5, 2019
Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies
Mari Kamiya1, Fumitaka Mizoguchi1, Kimito Kawahata1,2
1Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8519, Japan.
Abstract:
Muscle cell death in polymyositis is induced by CD8+ cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8+ cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of necroptosis suppresses not only CD8+ cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating polymyositis providing an alternative to current therapies directed at leukocytes.
Insights
Targeting necroptosis, a form of programmed cell death, in muscle cells offers a promising new therapy for polymyositis. Inhibiting this process reduces muscle injury and inflammation, providing an alternative to current treatments.
Area of Science:
- Immunology
- Cell Biology
- Neurology
Background:
- Polymyositis involves CD8+ cytotoxic T lymphocytes inducing muscle cell death.
- Muscle fiber injury may release pro-inflammatory molecules, exacerbating damage.
- Targeting muscle cell death presents a potential therapeutic strategy for polymyositis.
Purpose of the Study:
- To investigate the mechanisms of muscle cell death in polymyositis.
- To determine if inhibiting muscle cell death can ameliorate polymyositis.
- To explore necroptosis as a therapeutic target in polymyositis.
Main Methods:
- Analysis of human polymyositis muscle biopsy specimens.
- In vitro and in vivo models of polymyositis.
- Assessment of cell death pathways (FAS ligand-dependent necroptosis, perforin 1/granzyme B-dependent apoptosis).
- Evaluation of necroptosis inhibitors and anti-HMGB1 antibodies.
Main Results:
- Muscle fibers undergo FAS ligand-dependent necroptosis, while satellite cells and myoblasts undergo apoptosis.
- Inhibition of necroptosis reduced CD8+ T cell-induced myotube death and inflammatory molecule release (e.g., HMGB1).
- Treatment with necroptosis inhibitors or anti-HMGB1 antibodies improved muscle weakness, cell death, and inflammation.
Conclusions:
- Muscle cell necroptosis is a key mechanism in polymyositis.
- Targeting muscle cell necroptosis is a viable therapeutic strategy for polymyositis.
- This approach offers an alternative to leukocyte-focused therapies.
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