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（Duchenne Muscular Dystrophy, DMD）的肌肉萎缩由肌纤维脆性增加与再生不良引发，后者会导致慢性炎症及肌肉被纤维脂肪组织替代。我们的最新研究发现，源自ω-3脂肪酸的生物活性脂质消退素D2（Resolvin-D2）能够抑制炎症、促进肌肉再生，从而延缓疾病进程。相较于当前杜氏肌营养不良症的标准治疗药物糖皮质激素，该治疗策略具备诸多优势。但将生物活性脂质用作治疗药物时，也面临诸多技术难题，比如其稳定性较差、口服生物利用度低。
方法：本研究探讨了PSB-KD107——一种消退素D2受体Gpr18的合成激动剂——作为杜氏肌营养不良症治疗替代方案的潜力。
结果与讨论：实验证实，PSB-KD107可在体外提升患者诱导多能干细胞（induced pluripotent stem cell, iPSC）分化所得成肌细胞的肌源性能力。对经PSB-KD107处理的mdx成肌细胞进行RNA测序（RNAseq）分析后发现，其富集了与脂肪酸代谢、脂质生物合成、小分子生物合成及类固醇相关过程相关的生物学过程，同时也富集了过氧化物酶体增殖物激活受体、AMP活化蛋白激酶、哺乳动物雷帕霉素靶蛋白及鞘脂信号通路等信号通路。在体内实验中，对营养不良型mdx小鼠给予PSB-KD107治疗后，其炎症水平降低、肌发生过程增强且肌肉功能得到改善。PSB-KD107对肌肉功能的积极影响与消退素D2的效果相当。综上，本研究的发现为“生物活性脂质受体的合成类似物具备治疗杜氏肌营养不良症的潜力”提供了概念验证。