Sarcopenia refers to the progressive loss of skeletal muscle strength, quality, and mass during aging. It is accompanied by a loss of autonomy and increased mortality, with no curative treatment established to date. Since growth and differentiation factor 5 (GDF5) has previously been described as a modulator of muscle mass maintenance in various contexts, the authors sought to evaluate its therapeutic potential against age-related neuromuscular failure.
The proof of concept relied on GDF5 overexpression through AAV vector injection into the tibialis anterior muscle of aged mice (20 months), followed by molecular and functional analyses. The researchers then compared vastus lateralis muscle biopsies from young (21 to 42 years) and aged (77 to 80 years) human donors, in order to quantify in humans the markers altered by GDF5 in mice. The major effects of the factor were validated on immortalized human myotubes and Schwann cells. Finally, a preclinical study consisted of chronically treating aged mice for four months by systemic administration of recombinant protein (rGDF5).
GDF5 overexpression induced a 16.5% increase in muscle weight (P = 0.0471), associated with a higher proportion of large fibers (5000 to 6000 µm²), without triggering muscle regeneration. This gain in mass was accompanied by a 26.8% improvement in the rate of force generation (P = 0.0330) and enhanced neuromuscular connectivity. GDF5 further preserved neuromuscular junction morphology (38.5% increase in nerve terminal area, P < 0.0001) and stimulated the expression of reinnervation-related genes, notably Schwann cell markers (3.19-fold increase in S100b expression). Genome-wide transcriptomic analysis revealed a "rejuvenation" signature: 42% of age-dysregulated transcripts returned to juvenile expression levels after GDF5 overexpression. Prolonged systemic treatment with rGDF5 confirmed these benefits, counteracting muscle wasting, improving function (17.8% increase in absolute maximal force, P = 0.0079), and preventing neuromuscular junction degeneration. The age-related alterations observed in mice were also found in human biopsies, and the major effects of GDF5 were reproduced in human cells, suggesting possible efficacy in humans. Overall, these data lay the groundwork for evaluating the curative potential of GDF5 in clinical trials for sarcopenia and, eventually, other neuromuscular diseases.