The INTERACT project: CannabINoid recepTors as kEy playeRs in skeletAl musCle plasTicity

Sarcopenia is a critical matter of concern in an aging population. It impairs the elderly’s quality of life and imposes an enormous burden on the healthcare system. No therapies can fully overcome age-related skeletal muscle (SkM) wasting, although SkM is very plastic. Therefore, INTERACT explores the cannabinoid system as a novel target in combatting SkM wasting. More specific, we target cannabinoid receptor (CBR) 1 and CBR2 to improve the anabolic-catabolic balance, progenitor cell functioning and the regenerative capacity in old SkM. Our pilot data show that CBR1 expression is lower in old vs. young SkM, and that SkM CBR1 and CBR2 expression increase upon strength training in elderly. Interestingly, these increases correlate with changes in key markers of SkM anabolism (mTOR), catabolism (FOXO) and regenerative capacity (Pax7). Furthermore, in mice, CBR1 inhibition improves metabolism and SkM anabolism, while CBR2 stimulation improves SkM regeneration via anti-inflammatory and anti-fibrotic effects. Altogether, our data and recent advances indicate that CBRs are promising targets to improve the muscle phenotype. In this project, we will take this one step further and evaluate whether CBRs are effective to combat sarcopenia. Furthermore, we will study which mechanisms underlie the CBR-SkM interaction. These insights will uncover the role of CBRs as novel targets to improve key features of the old SkM phenotype and pave ways for novel therapies in SkM-devastating conditions.