Gpr18 agonist dampens inflammation, enhances myogenesis, and restores muscle function in models of Duchenne muscular dystrophy


Translational Research

Poster Number: 307


Junio Dort, University of Ottawa

Muscle wasting in Duchenne Muscular Dystrophy is caused by myofiber fragility and poor regeneration that leads to chronic inflammation and muscle replacement by fibrofatty tissue. Our recent findings demonstrated that Resolvins, a class bioactive lipids derived from omega-3 fatty acids, have 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 short-half life. Here, we explored the potential of synthetic agonist of bioactive lipid receptor, namely the Gpr18 agonist PSB-KD107, as a therapeutic alternative for Duchenne Muscular Dystrophy. We showed that PSB-KD107 can stimulate the myogenic capacity of human iPSC-derived myoblasts in vitro. RNAseq analysis revealed an enrichment in biological processes related to lipid metabolism, small molecule biosynthesis, and steroid-related processes in PSB-KD107-treated cells, as well as pathways related to fatty acid signaling such as Peroxisome proliferator-activated receptors, AMP-activated protein kinase, 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 compared to vehicle-treated mice. Overall, our findings identified a novel therapeutic target for the treatment of Duchenne Muscular Dystrophy.