A major goal of our laboratory is to decipher the mechanisms leading to muscle loss occurring during various physiological and pathological situations. This muscle mass loss leads to muscle weakness, contributes to the deterioration of patients' health, compromises treatments, and is associated with increased mortality. There is currently no treatment. Our goal is therefore to propose new therapeutic approaches that may prevent or mitigate muscle loss in catabolic conditions. We focus on the main proteolytic system controlling skeletal muscle mass, the Ubiquitin Proteasome System (UPS). The UPS is a highly complex and tightly regulated system comprising hundreds of enzymes. Before their degradation by the 26S proteasome, the UPS substrates are labeled by a ubiquitin chain catalyzed by a coordinated enzymatic cascade E1-E2-E3. E2-E3 couples (35 and > 600 respectively in mammals) are responsible for the UPS selectivity, the E3 ligase being responsible for substrate recognition while the E2 determines the type of ubiquitin chain linked to the substrate. Specific combinations of E2 and E3 enzymes are thus crucial for controlling muscle mass and represent potential clues for developing new strategies against atrophy. We combine complementary approaches to identify promising E2-E3 candidates involved in muscle atrophy: interactomic approaches (SplitGFP, Surface Plasmon Resonance, Micro-Scale Thermophoresis, etc.), cell biology, histology and physiology.