Musculoskeletal responses to spaceflight: mechanisms, countermeasures, and key gaps

Spaceflight and partial-gravity environments impose profound challenges to the human musculoskeletal system, driving rapid muscle atrophy, progressive bone loss, and tendon maladaptation. At the molecular level, unloading suppresses anabolic signaling, enhances proteolysis, and induces mitochondrial stress, whereas bone and tendon exhibit reduced extracellular matrix turnover and impaired mechanotransduction. 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.