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

Vanderbeke K.; Dalle S.; Koppo K. · Experimental gerontology · 2026

**Background & Methods** This is a narrative review synthesizing (pre)clinical studies examining the interplay between the endocannabinoid system (ECS), non-communicable diseases (NCDs), and skeletal muscle (SkM) degeneration. The authors analyzed alterations in ECS components (endocannabinoids, enzymes, receptors), effects of ECS modulation through receptor (ant)agonism or enzyme inhibition, and SkM degeneration symptoms across various NCD models and non-disease conditions. **Key Findings** - ECS composition is consistently altered across multiple NCDs including obesity, cancer cachexia, liver disease, kidney disease, cardiovascular disease, and inflammatory bowel disease, suggesting a dysregulation pattern common to these conditions. - Pharmacological or genetic ECS modulation improved several disease-related outcomes in preclinical models, including insulin resistance, liver fibrosis, and renal inflammation, with ECS modulation demonstrating potential to ameliorate SkM pathology (atrophy, impaired regeneration, inflammation, weakness) in various myopathy models. - The evidence supports a potential "ECS-disease-muscle axis" linking endocannabinoid dysregulation, NCD pathophysiology, and SkM degeneration, though direct validation of this hypothesis remains limited due to scarcity of clinical studies specifically evaluating ECS-based interventions in disease-associated muscle wasting. **Dosage & Administration** Not reported. This is a narrative review that summarizes existing literature rather than presenting original intervention data. **Safety & Adverse Effects** Not reported. The review does not comprehensively address safety profiles or adverse effects of ECS-targeted interventions. **Evidence Quality** This narrative review is predominantly based on preclinical data, representing a moderate level of evidence. Major limitations include: (1) predominance of animal model studies with limited human clinical data; (2) lack of direct studies evaluating ECS interventions specifically in disease-associated muscle wasting; (3) narrative rather than systematic review methodology, which may introduce selection bias; and (4) the hypothesis of an ECS-disease-muscle axis remains largely theoretical and requires further validation. The authors explicitly acknowledge that future research must generate human data directly testing ECS modulation in the context of disease-associated SkM degeneration to establish clinical relevance.

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