Duchenne muscular dystrophy (DMD) is a lethal disorder characterized by the lack of dystrophin, which is essential for muscle fibers integrity as its absence results in muscle necrosis followed by cyclic degeneration and regeneration. Initially, regeneration in DMD disease is supported by the proliferation and differentiation of muscle precursor cells, as satellite cells (SCs). However, they progressively exhausted, rendering muscle repair inefficient and leading to muscular dysfunction. Among the therapeutic strategies developed for DMD, clinical trials with AAV administration of microdystrophins (AAV-microDys) are underway and the first data indicate the potential of gene therapy as treatment to respond to unmet need for DMD. However, these approaches target the degenerating muscle, so their long-term success heavily depends on maintaining muscle mass for as long as possible. Emerging relevance, in terms of muscle mass preservation, is observed for Growth Differentiation Factor 5 (GDF5) which has been shown to prevent muscle mass loss and force decline during ageing. In addition, it has been described as a positive regulator of muscle homeostasis. We investigated its role in DMD progression using mdx mice and showed that GDF5 over-expression modulates regeneration process and induces hyperplasia. Of relevance, we propose to investigate the benefits of a combination of GDF5 with AAV-microdystrophin in improving gene therapy by preserving myofibers integrity and increasing muscle mass.