Convergent innate immune and regulated cell-death pathways in selected myopathies

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.