Human Skeletal Muscle Oxidative Capacity Is Improved By Cannabinoid Receptor 2 Antagonist (cb2)

Abstract

The endocannabinoid system plays an important role in whole body energy balance and glucose homeostasis. Dysregulation of the endocannabinoid system and up regulation of the cannabinoid receptors (CB) and circulating endocannabionoids, has been associated with obesity and type 2 diabetes. PURPOSE: to determine the effects of CB2 agonist and antagonist treatment on skeletal muscle substrate metabolism. METHODS: Male Sprague Dawley rats were fed 21% high fat diet (HFD) for 9 weeks to induce obesity. Following this rats were injected daily with CB2 agonist (AM1241; 3mg/kg bw), CB2 antagonist (AM630 0.3mg/kg bw) or control (saline) for 6 weeks. All animals were maintained on the same HFD. All animals were killed at the end of 15 weeks (n= 9-10 per group). Gastrocnemius muscle was dissected into red (oxidative muscle) and white (glycolytic muscle) tissue types. Citrate synthase activity was measured in red and white gastrocnemius muscle using citrate synthase enzymatic assay. Glycogen content was measured in soleus muscle by using Periodic acid-Schiff staining using immunohistochemistry technique, and quantified for glycogen content with image J software. RESULTS: CB2 antagonist treated animals significantly increased citrate synthase activity (14.43 ± 2.31 vs. 21.23 ± 2.26; p<0.02) in red gastrocnemius and showed no change (6.81 ± 0.91 vs. 6.47 ± 1.48; p<0.18) in white gastrocnemius muscle compared to control animals. CB2 agonist treatment did not change citrate synthase activity in red gastrocnemius (14.43 ± 2.31 vs.16.12 ± 2.42 AU; p<0.35) but tended to increase in white gastrocnemius muscle (6.81 ± 0.91 vs. 5.05 ± 1.23 AU; p<0.056). Glycogen content in soleus muscle was significantly greater in both CB2 antagonist (98.76 ± 2.96 vs. 71.28 ±2.28 AU; p<0.05) and CB2 agonist (101.25 ± 3.42 vs. 71.28 ± 2.28 AU; p<0.05) treated animals compared to HFD control. CONCLUSION: These data indicate that CB2 antagonist treatment improves skeletal muscle oxidative capacity and glycogen storage, especially in slow oxidative muscle.