Elevated circulating GDF11 and its role in age-related sarcopenia: insights from clinical, transcriptomic, and in vitro analyses.

INTRODUCTION: Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β (TGF-β) superfamily, has been implicated in aging and muscle homeostasis. However, its clinical relevance and mechanistic role in age-related sarcopenia remain incompletely defined. METHODS: Circulating GDF11 levels were quantified in 159 participants stratified by age (<60 vs. ≥60 years) and sarcopenia status. Propensity score matching (PSM) and multivariable logistic regression analyses were applied to identify factors independently associated with sarcopenia. Mendelian randomization (MR) and mediation analyses were conducted to explore potential causal relationships and indirect pathways linking physical activity, circulating GDF11, and sarcopenia. Bioinformatic analyses integrated skeletal muscle transcriptomic datasets and protein-protein interaction (PPI) networks. Mechanistically, differentiated C2C12 myotubes were treated with recombinant GDF11 (rGDF11), followed by assessment of canonical SMAD signaling and muscle atrophy-related markers, including phosphorylated SMAD3 (immunoblotting) and the E3 ubiquitin ligases Atrogin-1 and MuRF1 at both protein (immunoblotting) and transcript (RT-qPCR) levels. RESULTS: Circulating GDF11 concentrations were significantly higher in older adults than in younger individuals and were further elevated in participants with sarcopenia, both before and after PSM. Multivariable logistic regression identified circulating GDF11 as an independent risk factor for sarcopenia. MR analysis supported a causal protective effect of physical activity on sarcopenia-related traits, while mediation analysis indicated that circulating GDF11 partially mediated this association. Transcriptomic analyses demonstrated that GDF11 mRNA expression in skeletal muscle remained stable regardless of sarcopenia or exercise status, suggesting that elevated circulating GDF11 is unlikely to originate from skeletal muscle. PPI network analysis highlighted enrichment of activin receptor (ACVR)-SMAD signaling pathways. Consistent with these predictions, rGDF11 treatment activated SMAD3 phosphorylation and induced a dose-dependent upregulation of Atrogin-1 and MuRF1 at both the protein and mRNA levels in C2C12 myotubes, supporting activation of a pro-atrophic ubiquitin-proteasome program. CONCLUSION: Circulating GDF11 is elevated in individuals with sarcopenia and appears to partially mediate the protective effects of physical activity. Together with functional evidence of activation of catabolic signaling pathways, these findings support a contributory role of circulating GDF11 in age-related muscle loss.