Activités de recherche

Fighting against muscle atrophy: Understanding of the mechanisms & Development of countermeasures Muscle mass loss, or muscle atrophy, is observed in several physio-pathological situations (aging, physical inactivity, viral and bacterial infections, cancers, chronic diseases, muscular dystrophies…) and has harmful consequences for the patients. The maintenance of muscle mass relies on the balance between protein synthesis and proteolysis, both of which being fine-tuned by several interconnected signaling pathways. As with other research groups, we have contributed to deciphering the mechanisms involved in muscle atrophy. Our focus has been on understanding the role of ubiquitin-proteasome proteolysis, apoptosis, autophagy and mitochondrial homeostasis during physical inactivity or starvation (For examples see Vazeille et al. 2008, Slimani et al. 2012, Slimani et al. 2015, Deval et al. 2020). The molecular events involved in muscle atrophy were mainly identified using classical models of induced atrophy in rodents or humans. However, despite this thorough understanding, there is still no proven effective treatment (Peris-Moreno et al. 2021). 

In our team, we seized the opportunity to utilize a counter-model, namely the brown bear, which naturally resists muscle atrophy during hibernation. Actually, the brown bear remains inactive during its 5-7 month hibernation period in its den without eating. Despite facing this two strong inducers of muscle atrophy, i.e. prolonged physical inactivity and fasting, the brown bear exhibits a remarkable ability to preserve its muscle mass with little to no loss. This is in stark contrast to the significant muscle loss that would be experienced by humans or rodents under similar conditions.
By comparing classic models of susceptibility to muscle atrophy in rodents with the brown bear model of resistance to muscle atrophy, we have recently highlighted the role of the balance between the pro-atrophic TGFβ pathway and the hypertrophic BMP pathway in muscle mass preservation (Cussonneau et al. 2021, Cussonneau et al. 2022). 

Our objectives are to further explore the mechanisms involved in shifting the TGFβ/BMP balance towards a muscle mass maintenance phenotype. We aim to achieve this goal by utilizing the above comparative physiology approach and investigating the potential transfer of the bear’s ability to human muscle cells.
Identifying strategies of interest for preventing or counteracting muscle atrophy in catabolic situations is based on deciphering the mechanisms leading to muscle atrophy. We have highlighted the beneficial effect of certain nutritional (antioxidants, omega-3s) (Vazeille et al. 2012, Deval et al. 2016) and pharmacological strategies (Cussonneau et al. 2022). We also attach great importance to studying the fine mechanisms behind these beneficial effects observed with the use of a given strategy, in order to propose even more targeted, potentially effective strategies for preventing and/or counteracting muscle wasting and speeding up the subsequent recovery.

Mes 5 publications favorites :

• Cussonneau L et al. Induction of ATF4-Regulated Atrogenes Is Uncoupled from Muscle Atrophy during Disuse in Halofuginone-Treated Mice and in Hibernating Brown Bears. Int J Mol Sci. 2022 24:621. doi: 10.3390/ijms24010621.
• Cussonneau L et al. Concurrent BMP Signaling Maintenance and TGF-β Signaling Inhibition Is a Hallmark of Natural Resistance to Muscle Atrophy in the Hibernating Bear. Cells 2021 10:1873. doi: 10.3390/cells10081873.
• Peris-Moreno D et al.. Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control. Molecules 2021 26:407. doi: 10.3390/molecules26020407.
• Deval C et al. Mitophagy and Mitochondria Biogenesis Are Differentially Induced in Rat Skeletal Muscles during Immobilization and/or Remobilization. Int J Mol Sci. 2020 21:3691. doi: 10.3390/ijms21103691.
• Deval C et al.. Docosahexaenoic acid-supplementation prior to fasting prevents muscle atrophy in mice. J Cachexia Sarcopenia Muscle 2016 7:587-603. doi: 10.1002/jcsm.12103.

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