Plant-Derived Trans-β-Caryophyllene Boosts Glucose Metabolism and ATP Synthesis in Skeletal Muscle Cells through Cannabinoid Type 2 Receptor Stimulation

Skeletal muscle plays a pivotal role in whole-body glucose metabolism, accounting for the highest percentage of glucose uptake and utilization in healthy subjects. Impairment of these key functions occurs in several conditions including sedentary lifestyle and aging, driving toward hyperglycemia and metabolic chronic diseases. Therefore, strategies pointed to improve metabolic health by targeting skeletal muscle biochemical pathways are extremely attractive. Among them, we focused on the natural sesquiterpene and cannabinoid type 2 (CB2) receptor agonist Trans-β- caryophyllene (BCP) by analyzing its role in enhancing glucose metabolism in skeletal muscle cells. Experiments were performed on C2C12 myotubes. CB2 receptor membrane localization in myotubes was assessed by immunofluorescence. Within glucose metabolism, we evaluated glucose uptake (by the fluorescent glucose analog 2-NBDG), key enzymes of both glycolytic and oxidative pathways (by spectrophotometric assays and metabolic radiolabeling) and ATP production (by chemiluminescence- based assays). In all experiments, CB2 receptor involvement was tested with the CB2 antagonists AM630 and SR144528. Our results show that in myotubes, BCP significantly enhances glucose uptake, glycolytic and oxidative pathways, and ATP synthesis through a CB2-dependent mechanism. Giving these outcomes, CB2 receptor stimulation by BCP could represent an appealing tool to improve skeletal muscle glucose metabolism, both in physiological and pathological conditions.