Dort Junio, Orfi Zakaria, Fiscaletti Melissa, Campeau Philippe M, Dumont Nicolas A
CHU Sainte-Justine Research Center, Montreal, QC, Canada.
School of Rehabilitation, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
Front Cell Dev Biol. 2023 Aug 14;11:1187253. doi: 10.3389/fcell.2023.1187253. eCollection 2023.
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. 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. We showed that PSB-KD107 can stimulate the myogenic capacity of patient iPSC-derived myoblasts . 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. , 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.
杜氏肌营养不良症中的肌肉萎缩是由肌纤维脆弱和再生能力差导致的，这会引发慢性炎症，并使肌肉被纤维脂肪组织替代。我们最近的研究结果表明，源自ω-3脂肪酸的生物活性脂质Resolvin-D2有能力减轻炎症并刺激肌肉再生，从而缓解疾病进展。与目前治疗杜氏肌营养不良症的金标准药物糖皮质激素相比，这种治疗途径有许多优势。然而，将生物活性脂质用作治疗药物也面临许多技术挑战，比如它们的不稳定性和较差的口服生物利用度。在此，我们探索了Resolvin-D2受体Gpr18的合成激动剂PSB-KD107作为杜氏肌营养不良症治疗替代品的潜力。我们发现PSB-KD107可以刺激患者诱导多能干细胞衍生的成肌细胞的成肌能力。RNA测序分析显示，在PSB-KD107处理的mdx成肌细胞中，与脂肪酸代谢、脂质生物合成、小分子生物合成以及类固醇相关过程有关的生物学过程有所富集，同时还有过氧化物酶体增殖物激活受体、AMP激活的蛋白激酶、雷帕霉素靶蛋白以及鞘脂信号通路等信号通路。此外，用PSB-KD107治疗营养不良的mdx小鼠可减轻炎症、增强肌生成并改善肌肉功能。PSB-KD107对肌肉功能的积极影响与Resolvin-D2相似。总体而言，我们的研究结果提供了一个概念验证，即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。
