Régulation of the corticothropic axis during cancer cachexia in ApcMin/+ mice - Functional implication of the myostatin inhibition. (PhD B. Guégan)

• Summary

Scientific background. Cancer cachexia (CAC) is a catabolic syndrome characterized by a progressive decrease in muscle mass and strength with tumor growth. Recent work by our team (Martin et al. 2022) showed that the corticotropic axis (hypothalamic-pituitary-adrenal axis ; HPA) was activated in a murin model of CC (ApcMin/+ mice), triggering a specific glucocorticoid-dependant transcriptional response in muscle and liver tissues. Our data also showed that a myostatine knock-out gene prevented the occurrence of CC and corticotropic axis activation.

Research questions. In this PhD, we examine the mechanisms underlying HPA axis activation in CC. We hypothesize that central nervous system inflammation may play a critical role in instigating the systemic inflammatory response (observed in cachexia) which may trigger a transcriptional glucocorticoid-dependant response  in muscle and liver.

Objectives - Approach. We will determine in ApcMin/+ i) the level of hypothalamic inflammation, ii) whether an intraperitoneal injection of a soluble receptor of myostatine can prevent it (collaboration Olli RITVOS, University of Helsinki, Finland), a strategy used to block CC, and iii) whetheran  intracerebroventricular injection of pro-inflammatory cytokines (IL-1ß, IL-6) may induce a glucocorticoid-dependent transcriptional response in muscle and liver. Muscle function will also be studied in this context.

Expected results. The results of this project will enable us to determine whether hypothalamic inflammation regulates the corticotrope axis during CC, and to asses the impact of this regulation on muscle function and hepatic metabolism.