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

Abstract

Background As glucocorticoids induce muscle atrophy during the treatment course of polymyositis (PM), novel therapeutic strategy is awaited that suppresses muscle inflammation but retains muscle strength. We recently found that injured muscle fibres in PM undergo FASLG-mediated necroptosis, a form of regulated cell death accompanied by release of pro-inflammatory mediators, contributes to accelerate muscle inflammation and muscle weakness. Glucagon-like peptide-1 receptor (GLP-1R) agonists have pleiotropic actions including anti-inflammatory effects, prevention of muscle atrophy, and inhibition of cell death, in addition to anti-diabetic effect. We aimed in this study to examine the role of GLP-1R in PM and the effect of a GLP-1R agonist on in vivo and in vitro models of PM. Methods Muscle specimens of PM patients and a murine model of PM, C protein-induced myositis (CIM), were examined for the expression of GLP-1R. The effect of PF1801, a GLP-1R agonist, on CIM was evaluated in monotherapy or in combination with prednisolone (PSL). As an in vitro model of PM, C2C12-derived myotubes were treated with FASLG to induce necroptosis. The effect of PF1801 on this model was analysed. Results GLP-1R was expressed on the inflamed muscle fibres of PM and CIM. The treatment of CIM with PF1801 in monotherapy (PF) or in combination with PSL (PF + PSL) suppressed CIM-induced muscle weakness (grip strength, mean ± SD (g); PF 227 ± 6.0 (P < 0.01), PF + PSL 224 ± 8.5 (P < 0.01), Vehicle 162 ± 6.0) and decrease in cross-sectional area of muscle fibres (mean ± SD (μm 2 ); PF 1896 ± 144 (P < 0.05), PF + PSL 2018 ± 445 (P < 0.01), Vehicle 1349 ± 199) as well as the severity of histological inflammation scores (median, interquartile range; PF 0.0, 0.0-0.5 (P < 0.05), PF + PSL 0.0, 0.0-0.0 (P < 0.01), Vehicle 1.9, 1.3-3.3). PF1801 decreased the levels of inflammatory mediators such as TNFα, IL-6, and HMGB1 in the serum of CIM. PF1801 inhibited necroptosis of the myotubes in an AMP-activated protein kinase (AMPK)-dependent manner. PF1801 activated AMPK and decreased the expression of PGAM5, a mitochondrial protein, which was crucial for necroptosis of the myotubes. PF1801 promoted the degradation of PGAM5 through ubiquitin-proteasome activity. Furthermore, PF1801 suppressed FASLG-induced reactive oxygen species (ROS) accumulation in myotubes, also crucial for the execution of necroptosis, thorough up-regulating the antioxidant molecules including Nfe2l2, Hmox1, Gclm, and Nqo1. Conclusions GLP-1R agonist could be a novel therapy for PM that recovers muscle weakness and suppresses muscle inflammation through inhi biting muscle fibre necroptosis.

HMGB1 Promotes In Vitro and In Vivo Skeletal Muscle Atrophy through an IL-18-Dependent Mechanism

“…Several research groups have explored the associations between aberrant HMGB1 expression and muscle inflammation, weakness, and muscle fiber dysfunction [ 25 , 48 , 49 ]. Recent reports have shown that necroptosis in muscle cells contributes to the release of HMGB1 and thus accelerates muscle inflammation and subsequent muscle injury [ 50 , 51 ]. Activation of HMGB1/autophagy signaling is related to denervation-induced skeletal muscle atrophy [ 52 ], and the HMGB1/atrogin-1 axis has been shown to cause skeletal muscle dysfunction [ 53 ].…”

GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives

“…Furthermore, GLP-1 RAs have recently been shown to improve sarcopenic obesity in obese mice by influencing the skeletal muscle metabolism [ 140 , 141 , 142 ]. In addition to weight loss, semaglutide has been shown to lower the intramuscular accumulation of fat and promote protidosynthesis in these mouse models, increasing both mass and muscle function [ 140 ].…”

“…In addition to weight loss, semaglutide has been shown to lower the intramuscular accumulation of fat and promote protidosynthesis in these mouse models, increasing both mass and muscle function [ 140 ]. Furthermore, GLP-1 RAs have been shown to improve muscle wasting both by suppressing myostatin expression and promoting the expression of myogenic factors, as well as through anti-inflammatory and anti-apoptotic effects [ 141 , 142 ]. In light of the bidirectional relationship between NAFLD and sarcopenia and the significantly higher cardiovascular risk in obese sarcopenic patients compared to non-sarcopenic ones [ 143 ], GLP-1 RAs could guarantee additional direct benefits independent from weight loss and glycaemic control.…”

Novel nutritional strategies to prevent muscle wasting

“…The pleotropic effects of antidiabetic therapies have been harnessed in the experimental treatment of inflammatory muscular disorders [33]. This is of interest as sepsis and inflammation have long been associated as significant risk factors for ICU-AW [34].…”

“…TNF-alpha has been shown to up regulate skeletal muscle-specific UPS mediated proteolysis [39]. A recent study using a genetically-engineered glucagon-like peptide-1 receptor (GLP-1R) agonist in the treatment of polymyositis in an animal model suppressed myositis-induced muscle weakness, reduced inflammatory mediators (TNF alpha and IL-6), and ameliorated muscle atrophy [33]. Direct inhibitors of TNF-alpha, Il-6 and IL-1 have been trialled in cancer populations with mixed results in relation to muscle wasting and cachexia [41].…”