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Sarcopenia involves a progressive loss of skeletal muscle force, quality and mass during ageing, which results in increased inability and death; however, no cure has been established thus far. Growth differentiation factor 5 (GDF5) has been described to modulate muscle mass maintenance in various contexts. For our proof of concept, we overexpressed GDF5 by AAV vector injection in tibialis anterior muscle of adult aged (20 months) mice and performed molecular and functional analysis of skeletal muscle. We analysed human vastus lateralis muscle biopsies from adult young (21-42 years) and aged (77-80 years) donors, quantifying the molecular markers modified by GDF5 overexpression in mouse muscle. We validated the major effects of GDF5 overexpression using human immortalized myotubes and Schwann cells. We established a preclinical study by treating chronically (for 4 months) aged mice using recombinant GDF5 protein (rGDF5) in systemic administration and evaluated the long-term effect of this treatment on muscle mass and function. Here, we demonstrated that GDF5 overexpression in the old tibialis anterior muscle promoted an increase of 16.5% of muscle weight (P = 0.0471) associated with a higher percentage of 5000-6000 µm2 large fibres (P = 0.0211), without the induction of muscle regeneration. Muscle mass gain was associated with an amelioration of 26.8% of rate of force generation (P = 0.0330) and better neuromuscular connectivity (P = 0.0098). Moreover, GDF5 overexpression preserved neuromuscular junction morphology (38.5% of nerve terminal area increase, P < 0.0001) and stimulated the expression of reinnervation-related genes, in particular markers of Schwann cells (fold-change 3.19 for S100b gene expression, P = 0.0101). To characterize the molecular events induced by GDF5 overexpression during ageing, we performed a genome-wide transcriptomic analysis of treated muscles and showed that this factor leads to a 'rejuvenating' transcriptomic signature in aged mice, as 42% of the transcripts dysregulated by ageing reverted to youthful expression levels upon GDF5 overexpression (P < 0.05). Towards a preclinical approach, we performed a long-term systemic treatment using rGDF5 and showed its effectiveness in counteracting age-related muscle wasting, improving muscle function (17.8% of absolute maximal force increase, P = 0.0079), ensuring neuromuscular connectivity and preventing neuromuscular junction degeneration (7.96% of AchR area increase, P = 0.0125). In addition, in human muscle biopsies, we found the same age-related alterations than those observed in mice and improved by GDF5 and reproduced its major effects on human cells, suggesting this treatment as efficient in humans. Overall, these data provide a foundation to examine the curative potential of GDF5 drug in clinical trials for sarcopenia and, eventually, other neuromuscular diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)