LSD1 Inhibition Suppresses Glucocorticoid-induced Muscle Atrophy

Synthetic glucocorticoids (GCs) are used clinically for the treatment of chronic inflammatory and autoimmune disorders. However, prolonged GC therapy can result in serious side effects, including diabetes, osteoporosis, and muscle wasting. GCs exert their effects through interaction with the glucocorticoid receptor (GR), which binds chromatin to regulate transcriptional programs. It is now appreciated that these programs are cell-specific and shaped by the influence of GR-associated transcriptional co-regulators. Lysine-speciﬁc demethylase 1 (LSD1/KDM1A) is one of these co-regulators known to be involved in GC-dependent myogenic differentiation, making it an intriguing subject for further study with regard to potential therapeutic optimization of GCs.

Cai et al. present a detailed analysis of the relationship between GR and LSD1 as it relates to GC-mediated muscle atrophy (1). Using mouse knockout models in conjunction with protein-protein interaction assays, chromatin interrogation, and transcriptional analysis, the authors report a direct interaction between GR and LSD1 in male mouse myofibers. In addition, they show that LSD1 bridges GR-bound enhancers with NRF1 at active promoters to regulate at least 1000 genes (with most linked to protein degradation) in skeletal muscle at physiological GC levels. They then proceed to show that the GR/LSD1 complex is responsible for not only starvation-induced proteolysis gene expression in skeletal muscle, but that it also mediates synthetic GC (i.e., dexamethasone)-induced muscle atrophy. Implementing an established LSD1 inhibitor (CC-90011), the researchers demonstrate that LSD1 activity is essential for GR-dependent muscle wasting. Importantly, their results indicate that LSD1 inhibition can minimize muscle wasting without sacrificing the anti-inflammatory function of pharmacologic GC treatment. Together, not only does the Cai et al. study highlight the muscle-specific functions of GC/GR, it also spotlights the value of dissecting the mechanisms of GR/co-regulator relationships to reveal possible opportunities for therapeutic GC side effect amelioration.

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