Long-term effect of Resolvin-D2 on Duchenne muscular dystrophy

Duchenne Muscular Dystrophy (DMD) is the most common neuromuscular disorder in children, causing muscle weakness, chronic inflammation, and premature death. Glucocorticoids are the standard treatment but carry a rising risk of side effects like muscle atrophy with prolonged use. Recently, polyunsaturated omega-3 fatty acids (ω-3 PUFAs) and their downstream metabolites were shown to modulate inflammation in different pathophysiological conditions. In this study, we explored the effects of docosahexaenoic acid (DHA) and its metabolite resolvin-d2 (RvD2) on dystrophic muscle composition and function, using mouse models of DMD. We found that short-term administration of RvD2 dampens inflammation and increases the pool of myogenic progenitors, improving muscle regeneration. Our single-cell RNA sequencing indicates that the anti-inflammatory effect of RvD2 is maintained after six months. RvD2 regulates critical biological processes in macrophages to sustain its long-term anti-inflammatory effect, which is pivotal to mitigate DMD. This effect was more pronounced with RvD2 than glucocorticoids. DHA, as the RvD2 precursor, demonstrates the capacity to enhance muscle strength in dystrophic mice, an effect likely mediated, at least in part, by the subsequent generation and action of downstream metabolites, including RvD2. Altogether RvD2 represents a promising therapeutic alternative that offers sustained clinical benefits in alleviating DMD progression.