Background/Purpose: While glucocorticoids (GC) are the cornerstone of the treatment for polymyositis (PM), GC-induced myopathy is inevitable, which deteriorates muscle weakness. Therefore, novel therapeutic strategy that not only suppresses muscle inflammation but also improves muscle strength is awaited. Glucagon-like peptide-1 receptor (GLP-1R) agonists, which have been developed as an anti-diabetic therapy, have pleiotropic actions including anti-inflammatory effects, suppression of muscle wasting, and inhibition of cell death. We showed that the cell death of injured muscle fibers in PM is FASLG-mediated necroptosis, a form of regulated cell death accompanied with release of inflammatory mediators such as HMGB1. We also found that inhibition of necroptosis or HMGB1 ameliorated the muscle weakness and muscle inflammation in C protein-induced myositis (CIM), a murine model of PM. Accordingly, we hypothesized that GLP-1R agonists have beneficial effects on PM to recover muscle strength and to suppress muscle inflammation. The aims of this study are to examine the role of GLP-1R in PM and the effect of a GLP-1R agonist on PM models in vivo and in vitro.

Methods: Muscle specimens of PM patients and CIM were examined with immunohistological staining for the expression of GLP-1R. The effect of PF1801 (ImmunoForge, Seoul, South Korea), a GLP-1R agonist, on CIM was examined in monotherapy or in combination with prednisolone (PSL). C2C12-derived myotubes were treated with FAS ligand (FASLG) to induce necroptosis and used as an in vitro model of PM. The levels of HMGB1, TNF-α and IL-6 in the serum of CIM and the culture supernatant were measured by ELISA. The effect of PF1801 on the myotube necroptosis was examined using time lapse imaging and its effect on the activation of AMP-activated protein kinase (AMPK) and the expression of PGAM5 was assessed with western blotting. The levels of reactive oxygen species (ROS) were analyzed with CellROX® assay in vitro. The effect of PF1801 on the expression of antioxidant molecules was analyzed with quantitative real-time PCR in vitro.

Results: GLP-1R was expressed on the inflamed muscle fibers of PM and CIM. The treatment with PF1801 in monotherapy or in combination with PSL suppressed CIM-induced muscle weakness and the muscle weight loss as well as the severity of histological myositis while the monotherapy with PSL did not suppress muscle weakness and muscle weight loss. PF1801 decreased the levels of HMGB1, TNF-α and IL-6 in the serum of CIM. In vitro, PF1801 inhibited FASLG-induced myotube necroptosis and decreased the levels of HMGB1, TNF-α and IL-6 in the supernatant. The inhibitory effect of PF1801 on myotube necroptosis was dependent on the activation of AMPK. PF1801 activated AMPK and decreased the levels of PGAM5, which was crucial for FASLG-induced necroptosis of the myotubes. Furthermore, PF1801 upregulated the expression of antioxidant molecules including Nfe2l2, Hmox1, Gclm, and Nqo1 and suppressed FASLG-induced ROS accumulation in the myotubes.

Conclusion: GLP-1R agonist could be a novel therapy for PM that recover muscle weakness and suppress muscle inflammation through suppressing muscle fiber necroptosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/glucagon-like-peptide-1-receptor-agonist-suppresses-muscle-fiber-necroptosis-and-muscle-inflammation-and-ameliorates-muscle-weakness-in-experimental-polymyositis/