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Abstract Number: 1077

Glucagon-like Peptide-1 Receptor Agonist Suppresses Muscle Inflammation and Muscle Fiber Death, and Ameliorates Muscle Weakness in Experimental Polymyositis

Mari Kamiya1, Seon Uk Kim2, Jeong Yeon Kim3, Shinsuke Yasuda4, Eun Young Lee5 and Fumitaka Mizoguchi1, 1Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan, 2Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Jongno-gu, Seoul, Republic of Korea, 3Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 4Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Tokyo, Japan, 5Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

Meeting: ACR Convergence 2020

Keywords: Cell Death, Mouse Models, Other, Myositis

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Session Information

Date: Sunday, November 8, 2020

Session Title: Muscle Biology, Myositis & Myopathies Poster

Session Type: Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Glucocorticoids (GC) are the cornerstone of the treatment for polymyositis (PM). However, the treatment with GC causes GC-induced myopathy, which further deteriorates the muscle weakness. Therefore, new therapeutic strategy that not only suppresses muscle inflammation but also improves muscle strength is needed. 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 hypothesized that GLP-1R agonists have beneficial effects on PM to recover muscle strength and to suppress muscle inflammation. The aim of this study is to examine the effect of a GLP-1R agonist on in vitro and in vivo models of PM.

Methods: Muscle specimens of PM patients and C protein-induced myositis (CIM), a murine model of polymyositis, were examined with immunohistological staining for the expression of GLP-1R. The effect of PF1801 (ImmunoForge, Seaul, South Korea), a GLP-1R agonist, on CIM was examined in monotherapy (5 mg/kg body weight (BW)/day) or in combination with prednisolone (PSL, 20 mg/kg BW/day). The levels of HMGB1, TNF-α and IL-6 in the serum and the muscle were measured by ELISA. C2C12-derived myotubes were treated with FAS ligand (FASLG) to induce the myotube death. The effect of PF1801 on the myotube death was examined.

Results: Histological analysis of muscle specimens of PM patients and CIM revealed that GLP-1R was expressed on the plasma membrane of muscle fibers. The expression level of GLP-1R on the muscle fibers was high in the area where inflammatory infiltrates were observed. The treatment of CIM with PSL ameliorated CIM histologically in the levels of inflammatory infiltrate and the necrotic area, but did not ameliorate the muscle weakness nor muscle weight loss. The treatment with PF1801 in monotherapy (PF) or in combination with PSL (PF+PSL) suppressed CIM-induced muscle weakness (grip strength, mean ± SD (× 103 g/kg BW); PF 12.2 ± 1.0 (p< 0.0001), PF+PSL 12.7 ± 1.7 (p< 0.0001), Vehicle 8.4 ± 1.0) and the muscle weight loss (wet weight of quadriceps, mean ± SD (mg/g BW); PF 6.35 ± 0.72 (p< 0.01), PF+PSL 7.02 ± 0.42 (p< 0.001), Vehicle 5.16 ± 0.80) as well as the severity of histological myositis (histological score, median (interquartile range); PF 0.0 (0.0 to 0.5) (p< 0.05), PF+PSL 0.0 (0.0 to 0.0) (p< 0.001), Vehicle 1.9 (1.3 to 3.3)). The levels of HMGB1, TNF-α and IL-6 in the serum and the muscle were lower in PF1801-treated CIM mice than the mice treated with the vehicle control. In vitro, PF1801 inhibited FASLG-induced myotube death.

Conclusion: GLP-1R agonist could be a novel therapy to recover muscle weakness and to suppress muscle inflammation in PM.


Disclosure: M. Kamiya, None; S. Kim, None; J. Yeon Kim, None; S. Yasuda, Chugai Pharmaceutical Co., Ltd., 1, 2, GlaxoSmithKline Pharmaceuticals Ltd., 1, Mitsubishi Tanabe Pharma Co., 1, Astellas Pharma Inc., 1, Ono Pharmaceutical Co., Ltd., 1, Asahi Kasei Corporation, 1, 2, Bristol Myers Squibb, 1, 2; E. Lee, None; F. Mizoguchi, AbbVie, 2, 8, Astellas Pharma, 2, Bristol-Myers Squibb, 2, 8, Chugai Pharmaceutical, 2, 8, Daiichi Sankyo Company, 2, 8, Eisai, 2, 8, Eli Lilly and Company, 2, 8, ImmunoForge, 2, 5, Japan Blood Products Oraganization, 2, Mitsubishi Tanabe Pharma, 2, Novartis Pharma Japan, 2, Ono Pharmaceutical, 2, 8, Otsuka Pharmaceutical Factory, 2, Pfizer, 2, 8, Sanofi, 2, Takeda Pharmaceutical Company, 2, Teijin, 2, Asahi Kasei Pharma, 5, 8, Glaxo Smith Kline, 8.

To cite this abstract in AMA style:

Kamiya M, Kim S, Yeon Kim J, Yasuda S, Lee E, Mizoguchi F. Glucagon-like Peptide-1 Receptor Agonist Suppresses Muscle Inflammation and Muscle Fiber Death, and Ameliorates Muscle Weakness in Experimental Polymyositis [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/glucagon-like-peptide-1-receptor-agonist-suppresses-muscle-inflammation-and-muscle-fiber-death-and-ameliorates-muscle-weakness-in-experimental-polymyositis/. Accessed June 1, 2023.
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