A study conducted by the MOOVE* research team headed by France Pietri-Rouxel, in collaboration with several teams from the Institute and Sorbonne University, has just been published in Brain**. It focuses on the effects of chronic administration of a factor, GDF5, on age-related neuromuscular deficiency (sarcopenia) in mice.
Sarcopenia is an age-related disease involving excessive loss of skeletal muscle strength, quality and mass, leading to progressive physical disability. No cure for this has yet been developed. Growth differentiation factor 5 (GDF5) has been shown to modulate the maintenance of muscle mass in a variety of contexts.
Proof of concept
To achieve their proof of concept, the researchers in France Pietri-Rouxel’s team, notably Massiré Traoré and Sestina Falcone from the Centre de Recherche en Myologie, overexpressed GDF5 by AAV vector injection in the tibialis anterior (TA) muscle of 20-month-old adult mice, followed by molecular and functional analysis of the skeletal muscle.
The results showed that overexpression of GDF5 in the muscles of aged mice promoted an increase in muscle weight associated with a higher percentage of large muscle fibers. This gain in muscle mass was accompanied by improved neuromuscular connectivity. In addition, GDF5 overexpression preserved the morphology of the neuromuscular junction and stimulated the expression of reinnervation-related genes, in particular Schwann cell markers. Furthermore, the authors showed that these markers are altered in muscle biopsies (Vastus Lateralis) from elderly people (77-80 years) compared with those from young adults (21-42 years).
The potential of using GDF5 in humans was demonstrated by validating the main effects of GDF5 overexpression on immortalized human myotubes and human Schwann cells.
Characterization of molecular events induced by GDF5 overexpression during aging
The authors then carried out an analysis of gene expression profiles in young, aged and non-GDF5 overexpressing muscles. They showed that this factor leads to a “rejuvenating” transcriptomic signature in the muscles of treated aged mice. Indeed, 42% of the transcripts deregulated by aging returned to youthful expression levels after GDF5 overexpression.
Pre-clinical study
The authors conducted a preclinical study in which aged mice were chronically treated for 4 months with systemically administered recombinant GDF5 protein (rGDF5), and evaluated the long-term effect of this treatment. Results showed prevention of age-related muscle wasting, improved muscle function and neuromuscular connectivity, and maintenance of neuromuscular junction integrity.
Overall, these data provide an excellent basis for testing the therapeutic potential of GDF5 in clinical trials for sarcopenia and, potentially, in certain neuromuscular and motor neuron diseases.
* MOOVE research team – Muscle mass and function maintenance & optimization of AAV-based gene therapies, Center of Research in Myology.
