Glucocorticoid exposure during nutrient deprivation impairs recovery in postmitotic myotubes.

Sarcopenia is a degenerative condition marked by progressive loss of muscle mass and function. Despite its heterogeneous causes, it remains unclear which catabolic insults induce reversible versus irreversible forms of muscle damage. Here, we investigated the phenotypic and metabolic consequences of nutrient deprivation and glucocorticoid exposure using differentiated, post-mitotic murine myotubes as a standardized in vitro model, complemented by comparative transcriptomic profiling against human primary myotubes to assess the conservation of core myogenic programs. Nutrient deprivation and dexamethasone induced comparable early atrophic features, including reduced myotube diameter, disrupted contractility, loss of late myogenic markers, alterations in myosin isoform composition, and mitochondrial dysfunction, reflected by decreased cytochrome-C. We next examined the reversibility of atrophic damage. While refeeding partially restored the phenotype following nutrient deprivation alone, combined dexamethasone exposure induced a persistent, non-reversible state marked by sustained cytochrome-C depletion, loss of contractility and impaired anabolic signaling. Raman spectroscopy further revealed a selective depletion of membrane-associated lipids after dexamethasone, despite accumulation of neutral lipid droplets, indicating compartment-specific lipid remodeling. These findings demonstrate that starvation- and glucocorticoid-induced sarcopenic damage differ not only in severity but also in reversibility, providing mechanistic insight into why certain catabolic conditions may permanently compromise muscle recovery.