Abstract
Microgravity accelerates skeletal muscle degeneration, mimicking aging, yet its effects on human muscle cell function and signaling remain underexplored. Using a muscle lab-on-chip model onboard the International Space Station, we examined how microgravity and electrically stimulated contractions influence muscle biology and age-related muscle changes. Our 3D bioengineered muscle model, cultured for 21 days (12 days in microgravity), included myobundles from young, active and older, sedentary individuals, with and without electrically stimulated contraction. Real-time data collected within an autonomous Space Tango CubeLab(™) showed reduced contraction magnitude in microgravity. Global transcriptomic analysis revealed increased gene expression and particularly mitochondrial-related gene expression in microgravity for the electrically stimulated younger myobundles, while the older myobundles were less responsive. Moreover, a comparative analysis using a skeletal muscle aging gene expression database revealed that certain age-induced genes showed changes in expression in myobundles from the younger cohort when exposed to microgravity, whereas these genes remained unchanged in myobundles from the older cohort. Younger, electrically stimulated myobundles in microgravity exhibited higher expression of 45 aging genes involved in key aging pathways related to inflammation and immune function, mitochondrial dysfunction, and cellular stress; and decreased expression of 41 aging genes associated with inflammation, and cell growth. This study highlights a unique age-related molecular signature in muscle cells exposed to microgravity and underscores electrical stimulation as a potential countermeasure. These insights advance understanding of skeletal muscle aging and microgravity-induced degeneration, informing strategies for mitigating age-related muscle atrophy in space and on Earth.