Abstract
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.
Highlights
Aside from the many important biological functions such as insulating the internal organs, maintaining core body temperature, and supporting movement, skeletal muscle is a key site for glucose uptake and storage and plays a critical role in maintaining systemic glucose homeostasis through an interactive cross-talk with hepatic and adipose tissue [1,2]
As we have previously demonstrated that bicyclic sesquiterpene trans-β-caryophyllene (BCP) improves glucose uptake in C2C12 muscle cells [23], here, we investigated how this effect requires cannabinoid type 2 (CB2) receptor stimulation; for this purpose, we employed both AM630 and SR144528 as CB2 receptor antagonists in the glucose-uptake measurements
While cannabinoid type 1 (CB1) in skeletal muscle has been associated with a reduction in glucose uptake and fatty acid oxidation [33], Zheng et al found that CB2 receptor stimulation in C2C12 myotubes by trans-β-caryophyllene promotes lipid oxidation through the sirtuin 1/peroxisome proliferator co-activator receptor 1α (SRT1/PGC1α) pathway [31], paving the way for a role of this receptor in lipid metabolism, and more generally in the management of obesity and insulin resistance
Summary
Aside from the many important biological functions such as insulating the internal organs, maintaining core body temperature, and supporting movement, skeletal muscle is a key site for glucose uptake and storage and plays a critical role in maintaining systemic glucose homeostasis through an interactive cross-talk with hepatic and adipose tissue [1,2]. Since glucose transport into skeletal muscle regulates blood glucose concentration, it is a critical step in insulin-regulated glucose metabolic pathways such as glycolysis and glycogen synthesis. Dysfunctions in this process represent an important defect in the insulin action [2,4]. Impairment of glucose metabolism can occur in a range of conditions, from skeletal muscle disease like sarcopenia and cachexia, which are associated with a reduction in the amount of available muscle mass enough to maintain insulin-stimulated glucose uptake, to sedentary lifestyle and chronic metabolic diseases such as diabetes and obesity, characterized by the onset of insulin resistance [1,5,6,7]. This impairment is dangerous in cachectic cancer patients, where the low skeletal muscle mass could induce insulin resistance and decrease glucose clearance from the blood, resulting in more glucose disposable for the uptake by tumor cells, predisposing to poor clinical outcomes [8]
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