Sat0295 glucagon-Like Peptide-1 Receptor Agonist Ameliorated Muscle Weakness and Inflammation in Experimental Polymyositis

Abstract

Background:Polymyositis (PM) is a chronic inflammatory myopathy that impairs muscle functions. While the treatment with glucocorticoids (GC) has been the cornerstone of the treatment for PM to suppress immune-mediated muscle injury, some patients suffer from glucocorticoid-induced myopathy during the treatment, which further deteriorates the muscle weakness. It has been reported that significant disability and muscle weakness persist in a quarter of the patients even after successful treatment with the immunosuppressive therapy1. Ultimately, new therapeutic strategies to preserve and recover muscle strength as well as to suppress immune-mediated muscle injury are needed. Glucagon-like peptide-1 (GLP-1) is a peptide hormone with a variety of functions. Although GLP-1 receptor (GLP-1R) agonists have been developed as an anti-diabetic therapy to promote insulin secretion, emerging data suggest that they have pleiotropic actions including anti-inflammatory effects and suppression of muscle wasting2. We presumed that GLP-1R agonists have beneficial effect on PM to preserve and recover muscle strength.Objectives:To examine the effect of a GLP-1R agonist on C protein-induced myositis (CIM), a murine model of polymyositis3, in monotherapy or in combination with prednisolone (PSL).Methods:Muscle specimens of PM patients and CIM were examined with immunohistological staining for the expression of GLP-1R. The therapeutic effect of PF1801 (ImmunoForge), a GLP-1R agonist (5 mg/kg body weight (BW)/day), in monotherapy or in combination with PSL (20 mg/kg BW/day) on CIM was examined for grip strength, muscle weight and histological muscle inflammation.Results:GLP-1R was expressed on the plasma membrane of muscle cells of PM patients and CIM. The expression levels were high in the area where inflammatory infiltrates were observed. The treatment of CIM with PF1801 in monotherapy or in combination with PSL suppressed the CIM-induced decrease in grip strength on day 14. The combination therapy with PF1801 and PSL ameliorated the CIM-induced muscle weight loss in quadriceps, while the monotherapy with PF1801 or PSL did not. The histological analysis of muscle specimens on day 14 of CIM revealed that the muscle inflammation was suppressed by the treatments with PF1801, PSL, or the combination of PF1801 and PSL. None of the mice in the combination therapy group developed histologically evident myositis, while the myositis was observed in 90%, 40% and 40 % of the mice in vehicle treated group, PF1801 treated group, and PSL treated group, respectively. The necrotic area of the muscle in CIM was also reduced in the mice treated with PF1801, PSL, or the combination of PSL and PF1801. The CIM-induced increase in spleen weight was suppressed by PF1801, PSL, or the combination of PSL and PF1801. The additive effect of PSL and PF1801 on the suppression of CIM-induced increase in spleen weight was observed.Conclusion:PF1801 ameliorated CIM-induced muscle weakness and muscle inflammation in CIM. The combination therapy with PF1801 and PSL ameliorated CIM-induced muscle weight loss. PF1801 could be a novel therapy to recover muscle weakness and to suppress muscle inflammation in PM.References:[1]Bronner IM, et al.Ann Rheum Dis.2006;65:1456–61.[2]Hong Y, et al.J Cachexia Sarcopenia Muscle. 2019;10:903-18.[3]Sugihara T, et al.Arthritis Rheum. 2007;56:1304-14.Disclosure of Interests:Mari Kamiya: None declared, Seon Uk Kim: None declared, Jeong Yeon Kim: None declared, Yeong Wook Song: None declared, Eun Young Lee: None declared, Fumitaka Mizoguchi Grant/research support from: ImmunoForge, Consultant of: ImmunoForge