GDF5: A potential treatment for (neuro)-muscular diseases

Description

Abstract Among factors involved in muscle homeostasis, emerging relevance is observed for Growth Differentiation Factor 5 (GDF5) which we have shown to prevent age-related muscle mass loss and force decline. Indeed, we demonstrated that GDF5 overexpression in muscle during ageing induces muscle mass gain and improves neuromuscular connectivity and endplate morphology. In addition, we presented the characterization of the cellular and molecular effects of GDF5 in muscle during aging and showed its “rejuvenating signature”. Based on this proof of concept, we defined a cutting-edge therapeutic approach describing how the treatment with the recombinant GDF5 protein is able to counteract the age-related skeletal muscle wasting in mice and might have a strong curative potential on sarcopenia.

GDF5, because of its functions in muscle regeneration, could also be a good candidate for preserving muscle mass in neuromuscular diseases as Duchenne muscular dystrophy (DMD). 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. We investigated the role of GDF5 in DMD progression using mdx mice and showed that its 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.

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