Skeletal muscle mass is reduced during many diseases (cancer, sepsis, heart failure, kidney diseases, etc.) or physiological situations (disuse, aging), resulting in decreased strength, resistance to drug-treatments and increased mortality. The main cellular mechanism controlling muscle mass is the ubiquitin-proteasome system (UPS). Within the UPS, the E3 ligase MuRF1/TRIM63 targets for degradation several myofibrillar proteins, including the main contractile proteins: alpha-actin and myosin. However, MuRF1 depends on UBE2 ubiquitinconjugating enzymes (E2s) for ubiquitin chain formation on the substrates. A previous study identified five E2 enzymes (E2L3, E2E1, E2J1, E2J2 and E2G1) interacting with MuRF1[1], which represent enzyme couples potentially druggable for fighting against muscle atrophy. Here, we focused on E2L3 that exhibits high affinity towards MuRF1 (KD = ~50 nM) and E2E1, an E2 that depends on the presence of telethonin (a MuRF1 substrate), for efficient MuRF1 binding. References: [1] Polge et al. 2017. A muscle-specific MuRF1-E2 network requires stabilization of MuRF1-E2 complexes by telethonin, a newly identified substrate. JCSM. DOI: 10.1002/ jcsm.12249 [2] Polge et al. 2018. UBE2E1 is preferentially expressed in the cytoplasm of slow twitch fibers and protects skeletal muscles from exacerbated atrophy upon Dexamethasone treatment. Cells. DOI: 10.3390/cells7110214 [3] Peris-Moreno et al. 2021. UBE2L3, a Partner of MuRF1/TRIM63, Is Involved in the Degradation of Myofibrillar Actin and Myosin. Cells. doi: 10.3390/cells10081974. [4] Polge et al. 2011. Muscle actin is polyubiquitinylated in vitro and in vivo and targeted for breakdown by the E3 ligase MuRF1. FASEB J. doi: 10.1096/fj.11-180968.