Skeletal muscle loss is a detrimental side-effect of numerous
chronic diseases that dramatically increases mortality and morbidity. The alteration of protein homeostasis is generally due to increased
protein breakdown while,
protein synthesis may also be down-regulated. The
ubiquitin proteasome system (UPS) is a master regulator of skeletal muscle that impacts muscle contractile properties and metabolism through multiple levers like signaling pathways, contractile apparatus degradation, etc. Among the different actors of the UPS, the E3
ubiquitin ligases specifically target key
proteins for either degradation or activity modulation, thus controlling both pro-anabolic or pro-catabolic factors. The atrogenes MuRF1/TRIM63 and MAFbx/Atrogin-1 encode for key E3
ligases that target
contractile proteins and key actors of
protein synthesis respectively. However, several other E3
ligases are involved upstream in the
atrophy program, from signal transduction control to modulation of energy balance. Controlling E3
ligases activity is thus a tempting approach for preserving muscle mass. While indirect modulation of E3
ligases may prove beneficial in some situations of
muscle atrophy, some drugs directly inhibiting their activity have started to appear. This review summarizes the main signaling pathways involved in
muscle atrophy and the E3
ligases implicated, but also the molecules potentially usable for future
therapies.