Tokyo Medical and Dental University confirms suppression of muscle weakness that may help improve existing diabetes medications for inflammatory muscle disease

Glucagon-like peptide-1 receptor (GLP-1R) agonists are used clinically to treat diabetes and may be effective in treating inflammatory muscle diseases. A research group led by Associate Professor Shinsuke Yasuda and Assistant Professor Mari Kamiya of the Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, in collaboration with ImmunoForge, Inc. of South Korea, has shown that treatment with GLP-1R agonists in mice models of inflammatory myopathy (IM) recovers muscle weakness, muscle atrophy and muscle inflammation. "We hope to start the first two phases of clinical research around the beginning of next year," says Yasuda. The group's findings were published in the Journal of Cachexia, Sarcopenia, and Muscle.

IM is a chronic disease that causes progressive muscle weakness in the body and extremities and is designated as an intractable disease, with approximately 20,000 patients in Japan and roughly 2,000 new cases each year. While its cause is unknown, it is believed to be an autoimmune disease in which immune cells attack muscle cells.

Corticosteroids and immunosuppressive drugs are used to treat it, but since they are nonspecific in suppressing immunity, side effects such as infections are problematic. Also, corticosteroids induce steroid myopathy, which causes further muscle weakness. Furthermore, many patients do not respond to these treatments or have uncontrolled muscle inflammation.

Normally, GLP-1R is rarely expressed in muscle tissue, but the research group discovered about two years ago that it is expressed on the plasma membrane in muscle cells with inflammatory cell infiltrates derived from patients. On the other hand, GLP-1R agonists, which are clinically used to treat diabetes, have been reported to exert a variety of effects, such as suppression of muscle atrophy, cell death and anti-inflammation, in various experimental models. The research team therefore focused on the action of GLP-1R agonists, believing that they might be an effective treatment for IM, and tested their effects in patient-derived muscle tissue and in model mice and cell models.

When prednisolone (corticosteroid drug PSL) and a GLP-1R agonist (PF1801) were administered to a mouse model of the disease, the decrease in muscle mass could be suppressed for seven days with PSL but decreased after 14 days. In the group administered PF1801, muscle mass increased after 14 days, and the combined use of both agents had an even greater effect.

In IM, the inflammatory mediator HMGB1 released from the muscle cells that leads to necroptosis induces further inflammation. The concentration of HMGB1 in model mouse serum is markedly elevated, but the increase is suppressed when PF1801 is administered. This mechanism was tested in a cellular model and the research team found that PF1801 suppresses necroptosis via two mechanisms. One is the pathway mediated by the suppression of PGAM5 expression via AMPKα activation; the other is a pathway mediated by enhancing the expression of antioxidant molecules, such as Nfe2l2, and inhibiting the accumulation of reactive oxygen species (ROS), which are produced with necroptosis and have the effect of further promoting necroptosis. Inhibition of muscle cell necroptosis by these multiple pathways is the primary mechanism by which inflammation was improved in the mouse model.

Journal Information
Publication: Journal of Cachexia, Sarcopenia, and Muscle
Title: Amelioration of inflammatory myopathies by glucagon-like peptide-1 receptor agonist via suppressing muscle fibre necroptosis
DOI: 10.1002/jcsm.13025