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Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Convergent innate immune and regulated cell-death pathways in selected myopathies
Moe Yamashita1,2, Jaewoo Park1, Sehee Park3
1Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
Abstract:
Myopathies are a heterogeneous group of skeletal muscle disorders caused by genetic mutations or acquired insults, including inflammation, infection, endocrine imbalance, and toxic exposure. Myopathies affect a substantial number of individuals worldwide and are a significant cause of chronic muscle weakness and disability. Despite diverse etiologies, progressive myofiber injury and degeneration underlie the functional decline across disease subtypes. Accumulating evidence indicates that innate immune activation and regulated myofiber death pathways, including apoptosis, necroptosis, and pyroptosis, contribute to disease progression in selected genetic and acquired myopathies and may represent increasingly actionable therapeutic targets. This review focuses specifically on the interplay between innate immune signaling and the regulation of cell death pathways in skeletal muscle across diverse myopathies. We discuss pattern recognition receptors, inflammasome activation, and cytokine-driven pathways, such as tumor necrosis factor-alpha (TNF-α), type I interferons (IFNs), and interleukin (IL) family signaling, highlighting how these mechanisms amplify inflammation, impair regeneration, and promote myofiber degeneration. To illustrate category-specific mechanisms, we selected representative disorders from each major myopathy group, including Duchenne muscular dystrophy (DMD) as a prototypical DAMP-driven muscular dystrophy, myotonic dystrophy type 1 (DM1) as a model of secondary innate immune activation associated with RNA toxicity-induced cellular stress, dermatomyositis (DM) as a representative inflammatory myopathy, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated myopathy as a clinically relevant model of virus-related muscle involvement and systemic inflammation-associated muscle injury. By integrating evidence across these disease contexts, this review highlights convergent mechanisms in which innate immune dysregulation and regulated myofiber death drive muscle pathology and provide rational targets for mechanism-based therapeutic strategies.
Insights
Innate immune system activation and programmed cell death pathways drive muscle damage in various myopathies. Targeting these mechanisms offers new therapeutic strategies for muscle weakness and disability.
Area of Science:
- Muscle Biology
- Immunology
- Pathology
Background:
- Myopathies are diverse skeletal muscle disorders causing weakness and disability.
- Progressive myofiber injury and degeneration are common across myopathy subtypes.
- Innate immunity and regulated cell death pathways are increasingly recognized as key contributors to disease progression.
Purpose of the Study:
- To review the interplay between innate immune signaling and cell death regulation in skeletal muscle.
- To highlight how these mechanisms contribute to myofiber degeneration and disease progression.
- To identify potential therapeutic targets for myopathies.
Main Methods:
- Review of literature focusing on innate immune signaling and cell death pathways in myopathies.
- Discussion of pattern recognition receptors, inflammasome activation, and cytokine signaling (TNF-α, IFNs, ILs).
- Illustrative examples from Duchenne muscular dystrophy, myotonic dystrophy type 1, dermatomyositis, and SARS-CoV-2-associated myopathy.
Main Results:
- Innate immune dysregulation amplifies inflammation, impairs regeneration, and promotes myofiber degeneration.
- Specific pathways like TNF-α, IFNs, and ILs play critical roles in muscle pathology.
- Convergent mechanisms involving innate immunity and cell death are evident across different myopathy types.
Conclusions:
- Innate immune activation and regulated myofiber death are central to muscle pathology in myopathies.
- Understanding these pathways provides rational targets for mechanism-based therapeutic strategies.
- Targeting innate immunity and cell death offers promising avenues for treating muscle weakness and disability.
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