DataSheet1_Gpr18 agonist dampens inflammation, enhances myogenesis, and restores muscle function in models of Duchenne muscular dystrophy.PDF

Introduction: Muscle wasting in Duchenne Muscular Dystrophy is caused by myofiber fragility and poor regeneration that lead to chronic inflammation and muscle replacement by fibrofatty tissue. Our recent findings demonstrated that Resolvin-D2, a bioactive lipid derived from omega-3 fatty acids, has the capacity to dampen inflammation and stimulate muscle regeneration to alleviate disease progression. This therapeutic avenue has many advantages compared to glucocorticoids, the current gold-standard treatment for Duchenne Muscular Dystrophy. However, the use of bioactive lipids as therapeutic drugs also faces many technical challenges such as their instability and poor oral bioavailability.Methods: Here, we explored the potential of PSB-KD107, a synthetic agonist of the resolvin-D2 receptor Gpr18, as a therapeutic alternative for Duchenne Muscular Dystrophy.Results and discussion: We showed that PSB-KD107 can stimulate the myogenic capacity of patient iPSC-derived myoblasts in vitro. RNAseq analysis revealed an enrichment in biological processes related to fatty acid metabolism, lipid biosynthesis, small molecule biosynthesis, and steroid-related processes in PSB-KD107-treated mdx myoblasts, as well as signaling pathways such as Peroxisome proliferator-activated receptors, AMP-activated protein kinase, mammalian target of rapamycin, and sphingolipid signaling pathways. In vivo, the treatment of dystrophic mdx mice with PSB-KD107 resulted in reduced inflammation, enhanced myogenesis, and improved muscle function. The positive impact of PSB-KD107 on muscle function is similar to the one of Resolvin-D2. Overall, our findings provide a proof-of concept that synthetic analogs of bioactive lipid receptors hold therapeutic potential for the treatment of Duchenne Muscular Dystrophy.

引言：杜氏肌营养不良症中的肌肉萎缩由肌纤维脆弱和再生不良引起，导致慢性炎症和纤维脂肪组织的肌肉替代。我们的最新研究结果表明，Resolvin-D2，一种源自ω-3脂肪酸的生物活性脂质，具有抑制炎症和刺激肌肉再生以缓解疾病进展的能力。与目前杜氏肌营养不良症的标准治疗方法——糖皮质激素相比，这一治疗途径具有许多优势。然而，将生物活性脂质作为治疗药物也面临着许多技术挑战，如其不稳定性和较差的口服生物利用度。方法：在本研究中，我们探讨了PSB-KD107，一种Resolvin-D2受体Gpr18的合成激动剂，作为杜氏肌营养不良症治疗替代品的潜力。结果与讨论：我们证明了PSB-KD107可以刺激患者来源的iPSC衍生的肌原细胞的肌生成能力。RNA测序分析显示，PSB-KD107处理的mdx肌原细胞中富集了与脂肪酸代谢、脂质生物合成、小分子生物合成和类固醇相关过程相关的生物学过程，以及过氧化物酶体增殖物激活受体、AMP激活蛋白激酶、哺乳动物雷帕霉素靶点蛋白和鞘脂信号通路等信号通路。在体内实验中，用PSB-KD107治疗肌肉萎缩的mdx小鼠，结果显示炎症减轻、肌生成增强和肌肉功能改善。PSB-KD107对肌肉功能的影响与Resolvin-D2相似。总的来说，我们的研究结果表明，生物活性脂质受体的合成类似物在治疗杜氏肌营养不良症方面具有治疗潜力。