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Recent space-omics and cross-species studies, including rodent and Caenorhabditis elegans models, reveal that these catabolic responses are evolutionarily conserved and involve systemic pathways mediated by myokines, osteokines, and tendon-derived signals. Current countermeasure strategies primarily consist of structured exercise regimens with limited pharmacologic support. Although these strategies mitigate some loss, they fail to fully preserve musculoskeletal integrity, particularly tendon properties and microarchitectural bone quality. Key gaps remain in the development of tendon-specific interventions, integrated pharmacologic and exercise regimens, nutrition and dietary protocols, and methods for partial-gravity adaptation and safe re-entry. Leveraging real-time monitoring, individualized exercise programs, and systemic biomarker discovery through space omics presents major opportunities for next-generation, personalized countermeasures. This mini-review synthesizes current knowledge of musculoskeletal responses with a particular focus on tendon maladaptation and interorgan cross talk to spaceflight and partial gravity, highlights countermeasure efficacy and limitations, and identifies critical gaps that must be addressed to ensure astronaut health and performance during future missions. Insights from these studies also provide translational relevance for disuse atrophy, osteoporosis, and tendon injuries on Earth.<\/jats:p>","DOI":"10.1152\/ajpcell.00649.2025","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T12:30:57Z","timestamp":1762864257000},"page":"C1985-C1993","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Musculoskeletal responses to spaceflight: mechanisms, countermeasures, and key gaps"],"prefix":"10.1152","volume":"329","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0395-6967","authenticated-orcid":false,"given":"Brandon M.","family":"Roberts","sequence":"first","affiliation":[{"name":"Walter Reed Army Institute of Research","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2281-6479","authenticated-orcid":false,"given":"Colleen 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