GDF5 modulation of MuSC pool as a potential therapeutic benefit for DMD.

Duchenne muscular dystrophy (DMD) is a fatal disease caused by dystrophin deficiency, leading to degeneration of the entire musculature. To improve muscle pathophysiology and gene therapy for DMD, we investigated the potential of growth differentiation factor 5 (GDF5) in the DMD mdx mouse model. We showed that the overexpression of GDF5 in the muscle improved its histology, reduced inflammation, modulated regeneration, and induced the appearance of de novo fibers. We demonstrated that muscle satellite cells (MuSCs) are targeted by GDF5, which enhanced their proliferation and slowed down their myogenic commitment and finally their fusion. When combined with AAV-mediated microdystrophin gene therapy, the leading therapeutic strategy, GDF5 further increased the proportion of small microdystrophin-positive fibers compared to gene therapy alone. These findings highlight GDF5 as a promising modulator of DMD pathology and provide the first evidence of an additive effect of the combination of GDF5-based intervention and AAV-microdystrophin treatment.