Endocannabinoid system dysregulation in non-communicable diseases: implications for skeletal muscle health

Non-communicable diseases (NCDs) and their associated skeletal muscle (SkM) degeneration substantially contribute to morbidity and mortality. Interestingly, the endocannabinoid system (ECS) is increasingly recognized as an important regulator of both NCD pathophysiology and SkM plasticity. This narrative review summarizes the interplay between the ECS, NCDs and SkM degeneration - a potentially interesting triad that has not yet been comprehensively described, but may stimulate future research into the role of ECS-targeted interventions in the context of disease-associated SkM wasting. Therefore, we performed a narrative synthesis of (pre)clinical studies, focusing on alterations in ECS components (endocannabinoids, enzymes, receptors), the effects of ECS modulation (e.g. receptor (ant)agonism or enzyme inhibition), and SkM degeneration symptoms, across various (models of) NCDs. Additionally, the current literature on ECS modulation and SkM degeneration in non-disease models was summarized. The main findings show that ECS composition is consistently altered in different NCDs, including obesity, cancer (cachexia), liver disease, kidney disease, cardiovascular disease and inflammatory bowel disease. Pharmacological or genetic ECS modulation has been reported to improve several disease-related outcomes, e.g. insulin resistance, liver fibrosis and renal inflammation, predominantly in preclinical models. These NCDs also exhibit hallmarks of SkM degeneration, including atrophy, impaired regeneration, inflammation, and weakness. Notably, ECS modulation could ameliorate SkM pathology in various preclinical myopathy models, raising the hypothesis of an ECS-disease-muscle axis. However, this hypothesis requires further validation, as studies directly evaluating ECS-based interventions in disease-associated SkM degeneration remain limited. Future research should directly evaluate the existence of this potential ECS-disease-muscle axis by generating more (human) data on ECS modulation in the context of disease-associated muscle wasting.