Developing new strategies to limit TRIM63/MuRF1- mediated muscle protein loss


Institution information: University Clermont-Auvergne (UCA) and INRA, Clermont-Ferrand, France. Clermont-Ferrand is a vibrant student city and UCA is committed to developing educational programs for an international public (dual-award programs) and to enhancing its research at an international level. Since its creation, UCA has embraced the two main European political roadmaps for 2014-2020 through the Erasmus+ and Horizon 2020 programs.

Context: This position is part of a European Marie Skłodowska-Curie Action (see details in the joined PDF). This job includes an attractive 3-year full-time employment contract Enrolment in a PhD programme, supervision by recognized experts and access to state-of-the-art research, network-wide training activities, participation at workshops, on-line courses, schools and conferences in addition to local training activities in host labs.

Background: Protein degradation is the main determinant of muscle wasting and the ubiquitin proteasome proteolytic system (UPS) is a key player. Only specific E2-E3 combinations will lead to the degradation of specific substrates, e.g. contractile proteins. 

We previously showed that the muscle specific Trim63/MuRF1 is the main UPS actor targeting muscle contractile protein for degradation in catabolic states [1, 2]. Trim63/MuRF1 E3 enzyme is a good candidate for pharmacological treatment; however, it can target substrates from several metabolic pathways. We recently identified 5 E2 enzymes that interact with Trim63/MuRF1 [3-6]. The Ph.D. student objectives will be (i) to identify the muscle specific E2-E3 couple(s) implicated in muscle atrophy and (ii) to elaborate a pharmacological drug for inhibiting the implicated couple for fighting against patient’s weakness. We will first determine which E2-MuRF1 couple(s) specifically lead to contractile protein degradation in cellulo and in vivo. We will knockdown or overexpress (electroporation) the 5 E2-MuRF1 couples already identified and will address their impact on muscle structure (histological immunostaining and immunoblots) and function.

As a second step, the goal will be to search for pharmacological inhibitors to impede MuRF1-E2 interaction. Inhibitor screening will be performed by identifying amino acids residues involved in MuRF1-E2 interactions (hot spots approach, collaboration with chemists). E2s hot spots are already known and the ESR will identify their counterparts in Trim63/MuRF1. Identification of these residues will allow chemical synthesis of inhibitors. The inhibitory capacity to block specific MuRF1-E2 interactions will be performed in cultured cells using a split-GFP assay. Finally, the safety and the efficiency of inhibitors to block MuRF1-dependent degradation will be addressed by determining MuRF1 targets levels in skeletal muscle from catabolic mice.

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1. Polge, C., et al. (2011) Muscle actin is polyubiquitinylated in vitro and in vivo 
   and targeted for breakdown by the E3 ligase MuRF1. FASEB J. 25, 3790–3802.

2. Aniort, J., et al. (2016). Upregulation of MuRF1 and MAFbx participates to muscle 
   wasting upon gentamicin-induced acute kidney injury. 
   Int J Biochem Cell Biol, 79, 505-516.

3. Polge, C., et al. (2018). A muscle-specific MuRF1-E2 network requires stabilization 
   of MuRF1-E2 complexes by telethonin, a newly identified substrate. 
   J Cachexia Sarcopenia Muscle, 9(1), 129-145. 

4. Polge, C., 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, 7(11). 5. Polge, C., et al. (2016). 
   UBE2D2 is not involved in MuRF1-dependent muscle wasting during hindlimb suspension. 
   Int J Biochem Cell Biol, 79, 488-493.

6. Polge, C., et al. (2016). UBE2B is implicated in myofibrillar protein loss in 
   catabolic C2C12 myotubes. J Cachexia, Sarcopenia Muscle, 7(3), 377-87. 

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