Contractile proteins represent a major AA reservoir of the organism and their degradation by the ubiquitin proteasome system (UPS) requires 2 classes of enzymes...

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Contractile proteins represent a major AA reservoir of the organism and their degradation by the ubiquitin proteasome system (UPS) requires 2 classes of enzymes that, through their interaction, confer targeting selectivity: the E2s (≈40 members) generally bring the catalytic activity and the E3s (> 700 members) recognize the substrate, an E2 being able to interact with several E3s and vice versa.

There is currently no treatment to limit muscle wasting that occurs during catabolic states. Our goal is to better understand the degradation of contractile proteins by the UPS to open new avenues for fighting against muscle atrophy: 

• We aim to identify among the 14 poorly characterized muscular E2s, those involved in muscle atrophy. We already identified the E2 enzymes functionally interacting with MuRF1, the only E3 known to target contractile proteins.
• Since MuRF1 is the major actor of contractile protein degradation, we are currently looking for MuRF1 pharmacological inhibitors.

References

• 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
• Polge 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
• Polge et al. (2016) UBE2D2 is not involved in MuRF1-dependent muscle wasting during hindlimb suspension Int J Biochem Cell Biol
• Polge et al. (2015) UBE2B is implicated in myofibrillar protein loss in catabolic C2C12 myotubes J Cachexia Sarcopenia Muscle

Investigators
Agnès Claustre, Cécile Coudy-Gandilhon, Mélodie Malige, Dulce Peris-Moreno, Cécile Polge, Daniel Taillandier

We investigate the metabolic side effects of paracetamol treatment on amino acids/proteins homeostasis.

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Hypothesis
The eIF2α-ATF4 signaling pathway could contribute to paracetamol-induced sarcopenia


Context
Paracetamol is the first intention treatment of chronic pain. Its detoxification  occurs in the liver and utilises sulfates and glutathione, both of which are issued from cysteine (Cys) . The detoxification-induced siphoning of cysteine can reduce the bioavailbility of cysteine and aggravate sarcopenia.

Project
We aim to determine the role of the eIF2a-ATF4 signaling pathway could contribute to paracetamol-induced sarcopenia.

Perspectives
To optimize nutritional sulfur amino acid supplementation and methionine/cysteine ratio in order to promote the healthiest metabolic response to a large range of paracetamol treatments.



References

• Pickering et al. (2019) N-acetylcysteine Prevents Glutathione Decrease and Does Not Interfere With Paracetamol Antinociceptive Effect at Therapeutic Dosage: A Randomized Double-Blind Controlled Trial in Healthy Subjects Fundam Clin Pharmacol
• Mast et al. (2018) Impact of Medication on Protein and Amino Acid Metabolism in the Elderly: The Sulfur Amino Acid and Paracetamol Case Nutr Res Rev
• Mast et al. (2017) Dietary Supplementation With Cysteine Prevents Adverse Metabolic Outcomes of Repeated Cures With Paracetamol in Old Rats Br J Nutr
• Chaveroux et al. (2015) In Vivo Imaging of the Spatiotemporal Activity of the eIF2α-ATF4 Signaling Pathway: Insights Into Stress and Related Disorders Sci Signal
• Mast et al. (2014) Skeletal Muscle Wasting Occurs in Adult Rats Under Chronic Treatment With Paracetamol When Glutathione-Dependent Detoxification Is Highly Activated J Physiol Pharmacol

Investigators
Alain Bruhat, Valérie Cararro, Isabelle Papet