Many pathological conditions (cancers, sepsis...) are associated with cachexia resulting from increased catabolism and loss of appetite. Anorexia associated with pathology (secondary anorexia) is observed in nearly half of cancer patients, where chemotherapeutic treatments also generate metabolic deregulation and inhibition of food intake. Patients suffering from cachexia have systemic inflammation, increased energy requirement and altered amino acid metabolism. While the link between inflammation and loss of appetite is well established, the underlying molecular mechanisms are still poorly understood.

Hypothesis
Data from literature and our preliminary results led us to hypothesize that the stress signaling pathway eIF2a/ATF4 may play a role in the etiology of secondary anorexia.

• In the brain, we showed that this signalling contributes to disrupt the homeostatic regulation of food intake. (Maurin et al., Cell Metab 2005 ) and its pharmacological activation in the hypothalamus induces strong anorexia (Maurin et al. Cell Rep 2014 ).
• In peripheral tissues, eIF2a/ATF4 signaling can indirectly regulate appetite by controlling the expression of GDF15, a cytokine that is overexpressed in many diseases including cancers  (Baek & Eling, Pharmacol Ther 2019) and has an anorectic action via the activation of specific receptors in the brain stem (Hsu et al., Nature 2017).

• To characterize the development stages of atrophy in mouse models (fasting, physical inactivity...)
• To understand the mechanisms of resistance to atrophy in a hibernating mammal model
• To identify new molecular targets and key players in muscle mass control
• To identify innovative nutritional and/or pharmacological strategies to fight atrophy

• Comparative approaches of physiological and molecular responses in muscle and other tissues (protein metabolism, signalling pathway, mitochondrial homeostasis)
• Nutritional/pharmacological preconditioning to preserve muscle mass in vitro and in vivo
• Transfer of properties of hibernating bear serum to human cells

• Deval et al. (2020) Mitophagy and Mitochondria Biogenesis Are Differentially Induced in Rat Skeletal Muscles during Immobilization and/or Remobilization Int J Mol Sci
• Chazarin et al. (2019) Limited Oxidative Stress Favors Resistance to Skeletal Muscle Atrophy in Hibernating Brown Bears (Ursus Arctos) Antioxidants
• Chanon et al. (2018) Proteolysis inhibition by hibernating bear serum leads to increased protein content in human muscle cells Sci Rep
• Deval et al. (2016) Docosahexaenoic acid‐supplementation prior to fasting prevents muscle atrophy in mice J Cachexia Sarcopenia Muscle