Chemical Systems Biology Reveals Mechanisms of Dissociated Glucocorticoid Receptor Signaling

Glucocorticoids display remarkable anti-inflammatory activity, but their use is limited by undesirable on-target effects including insulin resistance and skeletal muscle atrophy. We used a chemical systems biology approach called Ligand Class Analysis (LCA) to examine ligands designed to alter the receptor through distinct structural mechanisms. These ligands displayed a full range of activity profiles, providing the variance required to identify ligand-specific gene expression and transcriptional coregulator interaction patterns that were highly predictive of their effects on myocyte glucose disposal and protein balance. Anti-inflammatory effects were linked to inhibition of glucose disposal in skeletal muscle but not to muscle atrophy. This approach successfully predicted dissociated activity in vivo, identifying compounds that were muscle sparing or anabolic for protein balance and mitochondrial potential. LCA defines the mechanistic links between the ligand-receptor interface and the physiological outcomes of the ligands, a general approach that can be applied to any ligand-regulated allosteric signaling system. Steroid-deprived C2C12 myotubes were compared by nascent RNA-seq after a 2-hour treatment with vehicle or Dexamethasone