Figure 7. Atrogene upregulation is a central mechanistic hub underlying the damaging actions of GC excess in bone, skeletal muscle, and the heart.

Interfering with the E3 ubiquitin (ub) ligase (atrogene) pathway via increased vitamin D₃ (Vit D₃) signaling blocks the deterioration of tissue structure and function in the musculoskeletal and cardiac systems. Likewise, usage of proteasomal inhibitor carfilzomib preserves bone and skeletal muscle in the setting of excessive GC, indicating that proteasomal-driven protein catabolism mediates musculoskeletal atrophy by GC. Likewise, genetic loss of function of MuRF1-mediated ubiquitination protects against adverse GC actions in muscle tissues (both skeletal and cardiac) and initially protects bone. Overall, these in vivo findings demonstrate (a) that the atrogene pathway is commonly upregulated in excessive GC disease in 3 distinct and highly specialized tissues, bone, skeletal muscle, and the heart; (b) that increased vitamin D₃ signaling preserves tissue structure and function by interfering with GC actions on the atrogene pathway in each of these organs; and (c) that MuRF1’s molecular ubiquitination function is the mechanistic contributor to the loss of tissue structure and function in skeletal and cardiac muscle tissues.