Integrated Cross-Species Translation and Biophysical Multi-Scale Modeling Links Molecular Signatures and Locomotory Phenotypes in Spaceflight-Induced Sarcopenia

Age-related skeletal muscle deterioration, referred to as sarcopenia, poses significant risks to astronaut health and mission success during spaceflight, yet its multisystem drivers remain poorly understood. While terrestrial sarcopenia manifests gradually through aging, spaceflight induces analogous musculoskeletal decline within weeks, providing an accelerated model to study conserved atrophy mechanisms. Here, we introduced an integrative framework combining cross-species genetic analysis with physiological modeling to understand mechanistic pathways in space-induced sarcopenia. By analyzing rodent and human datasets, we identified conserved molecular pathways underlying microgravity-induced muscle atrophy, revealing shared regulators of neuromuscular signaling including pathways related to neurotransmitter release and regulation, mitochondrial function, and synaptic integration. Building upon these molecular insights, we developed a physiologically grounded central pattern generator model that reproduced spaceflight-induced locomotion deficits in mice. This multi-scale approach established mechanistic connections between transcriptional changes and impaired movement kinetics while identifying potential therapeutic targets applicable to both spaceflight and terrestrial aging-related muscle loss.