GDF5 as a rejuvenating treatment for age-related neuromuscular failure

• DOI: 10.1093/brain/awae107
• Publication Date: 2024-04-08T07:49:26Z
• Authors: Massiré Traoré; Chiara Noviello; Amélie Vergnol; Christel Gentil; Marius Halliez; Lucile Saillard; Maxime Gelin; Anne Forand; Mégane Lemaitre; Zoheir Guesmia; Bruno Cadot; Eriky Caldas de A...; Benjamin Marty; Nathalie Mougenot; Julien Messéant; Laure Strochlic; Jeremy Sadoine; Lofti Slimani; Ariane Jolly; Pierre De la Grange; Jean-Yves Hogrel; France Pietri-Rouxel; Sestina Falcone
• Keywords: 03 medical and health sciences; 0302 clinical medicine; [SDV]Life Sciences [q-bio]

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