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Cécile Polge

5
Documents

Présentation

**Proteolysis plays a key role in controlling muscle growth and atrophy**. However, the regulatory mechanisms by which nutrients, hormones and/or physical activity control proteolysis are still poorly understood. The **Ubiquitin Proteasome System (UPS)** is responsible for the breakdown of the major contractile proteins and is a highly complex and tightly regulated proteolytic system comprising hundreds of enzymes. Understanding the regulatory mechanisms that control muscle mass is compulsory to ultimately preserve muscle strength during aging and many pathological wasting conditions like cancers, infections, trauma, renal failure, etc. Therefore, **our final goal** is to propose new therapeutic approaches that may **prevent or limit muscle loss in catabolic conditions and/or improve muscle recovery following atrophying situations.** These studies are of obvious clinical interest for reducing the length of hospitalizations and for improving treatments efficiency, and thus should ultimately result in decreased health care costs. As a key player in muscle atrophy, the Ubiquitin Proteasome System (UPS) is a potential target for fighting against an exacerbated proteolysis. UPS substrates are labeled by a ubiquitin chain catalyzed by a **coordinated enzymatic cascade E1-E2-E3**. The polyubiquitinated proteins are then degraded by the 26S proteasome. The UPS regulates numerous cellular processes and the proteasome is common to all the proteins to be degraded. Thus, targeting the proteasome would inhibit the whole UPS-linked cellular protein degradation and would be highly toxic for cells. By contrast, E2-E3 couples (35 and > 600 respectively) are responsible for UPS selectivity, the E3 ligase being responsible for the recognition of the substrate while the E2 defines the type of ubiquitin chain linked to the substrate. Thus, E2-E3 couples represent a more promising target for fighting against muscle atrophy. **Research activities** We demonstrated that α-actin is a UPS substrate in cultured myotubes and in human biopsies. In addition, the muscle-specific E3 ligase MuRF1 targets the myofibrillar actin pool (Polge et al, FASEB J. 2011). We demonstrated that UBE2B, an E2 highly expressed in atrophying skeletal muscle, targets the cytoplasmic pool of actin for MuRF1-independent degradation, which suggests that different E2-E3 couples target distinct pools of actin (Polge et al, JCSM 2016a). We determined that UBE2D2 is not involved in MuRF1-dependent muscle wasting during hindlimb suspension (Polge et al, IJBCB 2016b). Using complementary approaches, we recently identified five E2 enzymes interacting with MuRF1 (E2E1, E2G1, E2J1, E2J2, and E2L3) (Polge et al, JCSM 2018). We showed that telethonin, a newly identified MuRF1 substrate, governed the affinity between MuRF1 and E2E1 or E2J1 (Polge et al, JCSM 2018). We are currently studying the capacity of E2-MuRF1 duos to target the main contractile proteins (actin, myosin heavy chains, …) both in vitro and in vivo (Polge et al, Cells 2018). We routinely use in vitro approaches and various cellular (C2C12, L6, …), animal (rodents) and human (biopsies) catabolic models. We are specialized in protein-protein interaction studies using complementary approaches like yeast 2- and 3-hybrid and SPR (Biacore).

Publications

"julien-aniort"
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Muscle wasting in patients with end‐stage renal disease or early‐stage lung cancer: common mechanisms at work

Julien Aniort , Alexandre Stella , Carole Philipponnet , Anaïs Poyet , Cécile Polge
Journal of Cachexia, Sarcopenia and Muscle, 2019, 10 (2), pp.323-337. ⟨10.1002/jcsm.12376⟩
Article dans une revue hal-02167448v1
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UBE2E1 Is Preferentially Expressed in the Cytoplasm of Slow-Twitch Fibers and Protects Skeletal Muscles from Exacerbated Atrophy upon Dexamethasone Treatment (vol 7, 214, 2018)

Cécile Polge , Julien Aniort , Andrea Armani , Agnes Claustre , Cécile Coudy-Gandilhon
Cells, 2018, 7 (12), ⟨10.3390/cells7120242⟩
Article dans une revue hal-02622197v1
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UBE2E1 Is Preferentially Expressed in the Cytoplasm of Slow-Twitch Fibers and Protects Skeletal Muscles from Exacerbated Atrophy upon Dexamethasone Treatment

Cécile Polge , Julien Aniort , Andrea Armani , Agnes Claustre , Cécile Coudy-Gandilhon
Cells, 2018, 7 (11), ⟨10.3390/cells7110214⟩
Article dans une revue hal-01958290v1

A muscle-specific MuRF1-E2 network requires stabilization of MuRF1-E2 complexes by telethonin, a newly identified substrate.

Cécile Polge , Stéphanie Cabantous , Christiane Deval , Agnes Claustre , Antoine Hauvette
Journal of Cachexia, Sarcopenia and Muscle, 2018, 1 (1), pp.129-145. ⟨10.1002/jcsm.12249⟩
Article dans une revue hal-01730002v1

Upregulation of MuRF1 and MAFbx participates to muscle wasting upon gentamicin-induced acute kidney injury

Julien Aniort , Cécile Polge , Agnes Claustre , Lydie Combaret , Daniel Bechet
International Journal of Biochemistry and Cell Biology, 2016, 79, pp.505-516. ⟨10.1016/j.biocel.2016.04.006⟩
Article dans une revue hal-01512019v1