Integrative transcriptomics identifies an 18-gene candidate blood-accessible biomarker panel for longitudinal monitoring of spaceflight-induced muscle atrophy.

Skeletal muscle atrophy is a critical physiological risk during long-duration spaceflight, yet candidate blood-accessible transcriptomic biomarkers for longitudinal monitoring remain unavailable. We developed an integrative multi-mission framework combining a primary discovery transcriptome from THP-1 monocytic cells exposed to International Space Station (ISS) microgravity (GEO: Sci. Adv. 2026 (https://doi.org/10.1126/sciadv.adw7832, Data S1-S10); NASA OSDR: Al-Ahmadi et al. 2026; n = 8 spaceflight, 8 ground control) - yielding 4,522 spaceflight-differentially expressed genes (SDEGs) - with a PRISMA-compliant meta-analysis of 46 verified spaceflight studies, producing a 726-gene consensus set. Cross-referencing these datasets identified 103 intersection genes; application of our Integrated Concordance Score (ICS) nominated an 18-gene candidate biomarker panel nominated across six external missions. Orthogonal cross-tissue concordance analysis using six C2C12 myotube simulated-microgravity datasets demonstrated Pearson r = 0.79 (95% CI 0.52-0.92, p < 0.001), with a conserved stress module achieving r = 0.88; complementary concordance in human primary skeletal myotubes confirmed tri-model directional concordance for 13 stress-module genes. Gold-tier biomarkers (TNNT3, TRIM63, ACTC1, IGF2; ICS ≥ 8.0) showed ≥83% multi-mission concordance. Temporal modelling informs a preliminary two-tier fortnightly/monthly monitoring framework aligned with measured saturation kinetics, and the prioritised panel converges on coordinated ubiquitin-proteasome activation, AKT-mTOR-FOXO3a remodelling, E2F suppression, and sarcomeric reprogramming. Integrated drug-gene analysis identified bimagrumab combined with leucine as the top predicted prioritised countermeasure pair (computational Bliss = 2.8). These findings establish a proposed candidate blood-accessible biomarker framework for periodic muscle health surveillance during long-duration human spaceflight, available prospective validation in astronaut blood samples. The unit of analysis was the analytical contrast (spaceflight vs. matched ground control), not the publication. Cross-platform harmonization was performed via gene-level mapping and rank-based normalization.