Abstract
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 spaceflight-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.
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Data availability
All human transcriptomics data used from the study are available through Gene Expression Omnibus with accession numbers GSE14901, GSE111006, GSE111010, and GSE111016. Mouse transcriptomics data is available through the NASA Open Science Data Repository with accession OSD-103. Mouse behavioral data is available with accession OSD-478 on the NASA Open Science Data Repository.
Code availability
All code used for the analysis is available at https://github.com/Brubaker-Lab/MouseFLTandHumanSA. All supplementary information, including figures and data, is also made available on the GitHub repository.
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Acknowledgements
B.K.B. and H.F.K. are supported by the NSF GRFP (DGE-1842166). D.D.C. is supported in part by the DARPA Young Faculty Award (Army Research Office Contract W911NF21103272) and National Science Foundation (Awards 1944394 and 2149946). D.K.B. is supported by an award from the Good Ventures Foundation, Open Philanthropy, and start-up funds from Case Western Reserve University.
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B.K.B.: Conceptualization, data curation, formal analysis, investigation, methodology, visualization, writing-original draft, writing-review & editing. H.F.K.: Conceptualization, data curation, formal analysis, investigation, methodology, visualization, writing-original draft, writing-review & editing. J.H.P.: Data curation, methodology, writing-review & editing. K.J.: Project administration, resources, writing-review & editing. D.D.C.: Conceptualization, methodology, project administration, resources, funding acquisition, writing-review & editing. D.K.B.: Conceptualization, funding acquisition, methodology, project administration, resources, writing-review & editing.
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Ball, B.K., Khan, H.F., Park, J.H. et al. Integrated cross-species translation and biophysical multi-scale modeling links molecular signatures and locomotory phenotypes in spaceflight-induced sarcopenia. npj Microgravity (2026). https://doi.org/10.1038/s41526-025-00557-x
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DOI: https://doi.org/10.1038/s41526-025-00557-x
