SUMOylation modulates glucocorticoid-induced muscle toxicity in cell and mouse models

Prolonged glucocorticoid (GC) exposure is a clinically relevant cause of skeletal muscle atrophy through activation of glucocorticoid receptor (GR)-dependent catabolic transcriptional programs, including those mediated by Krüppel-like factor 15 (KLF15). However, the post-translational regulatory mechanisms that modulate the magnitude of GC-driven catabolic signaling in skeletal muscle remain incompletely understood. In this study, we investigated the role of SUMOylation as a stress-responsive post-translational regulatory mechanism in GC-induced muscle toxicity. Pharmacological modulation of SUMOylation was examined using the SUMOylation activator N106 in differentiated C2C12 myotubes and in a DEX-treated mouse model, both subjected to dexamethasone (DEX) treatment. Morphological, transcriptional, and functional parameters were assessed in vitro and in vivo, and the requirement for SUMO conjugation was interrogated using the SUMO E1 inhibitor TAK981. DEX exposure was associated with reduced SUMO-conjugated protein levels and induced a robust GR-KLF15-dependent catabolic transcriptional response in skeletal muscle cells and tissues. Enhancement of SUMOylation by N106 attenuated DEX-induced reductions in myotube diameter and muscle fiber cross-sectional area and suppressed the induction of muscle atrogenes (Fbxo32, Trim63) and metabolic enzymes (Pdk4, Bcat2). In vivo, N106 mitigated DEX-associated impairments in muscle function, including grip strength and treadmill endurance. In contrast, pharmacological inhibition of SUMOylation by TAK981 enhanced GC-induced catabolic gene expression, supporting an important role for SUMO conjugation in regulating skeletal muscle stress responses. Collectively, these findings identify SUMOylation as a post-translational regulatory layer that constrains GR-mediated catabolic transcription under GC stress. Chemical modulation of the SUMOylation pathway influences the severity of GC-induced muscle atrophy, highlighting SUMOylation as an important determinant of skeletal muscle susceptibility to GC-induced toxicity.