Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

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.

Amelioration of inflammatory myopathies by glucagon‐like peptide‐1 receptor agonist via suppressing muscle fibre necroptosis

“… 5 We also found that necroptosis contributes to the inflammation of PM through the release of HMGB1, one of the family of DAMPs. 5 …”

“…The cells undergo necroptosis subsequently release inflammatory molecules including intracellular damage‐associated molecular patterns (DAMPs) and cytokines, which cause tissue inflammation and secondary tissue damage 4 . We have previously shown that the form of cell death of muscle fibres in PM is FASLG‐mediated necroptosis using human muscle biopsy specimens of PM patients and models of PM in vitro and in vivo 5 . We also found that necroptosis contributes to the inflammation of PM through the release of HMGB1, one of the family of DAMPs 5 …”

Suppression of the necroptotic cell death pathways improves survival in Smn2B/− mice

“…Necroptosis has been shown to be involved in skeletal muscle pathology of other diseases (Bencze et al, 2018 ; Morgan et al, 2018 ; Kamiya et al, 2022 ). A first study in dystrophin-deficient muscles, identified RIPK3 as a key player in the degeneration of skeletal muscle (Morgan et al, 2018 ).…”

“…Ripk3 ablation in the mdx mouse model improved motor function, which was attributed to a reduction in muscle degeneration, inflammation, and fibrosis (Morgan et al, 2018 ). In the context of inflammatory myopathies, suppression of necroptosis improved muscle weakness and cell death via reduction of pro-inflammatory cytokines and the NF-κβ pathway (Kamiya et al, 2022 ). As a result of necroptotic pathway ablation, apoptosis of muscle satellite cells was reduced (Kamiya et al, 2022 ).…”

“…In the context of inflammatory myopathies, suppression of necroptosis improved muscle weakness and cell death via reduction of pro-inflammatory cytokines and the NF-κβ pathway (Kamiya et al, 2022 ). As a result of necroptotic pathway ablation, apoptosis of muscle satellite cells was reduced (Kamiya et al, 2022 ). The beneficial effects of suppressing necroptosis thereby seem to be restricted to chronic muscle impairments since inhibition of necroptosis led to significant muscle regeneration defects in the context of acute toxin induced muscle injury (Zhou et al, 2020 ).…”