Azilsartan ameliorates angiotensin II-induced skeletal muscle atrophy via AT1R-mediated PI3K/AKT/FOXO3a signaling pathway.

Background: Sarcopenia is a progressive age-related skeletal muscle disorder characterized by the loss of muscle mass, strength, and physical performance. Increasing evidence suggests that activation of the renin-angiotensin system (RAS) contributes to muscle wasting through promotion of protein degradation and impairment of anabolic signaling. Azilsartan (AZL), a highly selective angiotensin II type 1 receptor (AT1R) blocker, has demonstrated pleiotropic effects beyond blood pressure control. However, its effects on skeletal muscle atrophy and the underlying mechanisms remain incompletely understood. Methods: We combined a prospective observational study with mechanistic investigations in animal and cellular models. Older adults with hypertension and sarcopenia received AZL (40 mg/day) or other antihypertensive therapies for 6 months, and muscle strength, gait speed, and appendicular skeletal muscle mass were assessed. Moreover, Ang II-induced skeletal muscle atrophy models were established in mice and C2C12 myotubes to evaluate the effects of AZL on muscle morphology and signaling pathways. Results: models and were further attenuated by the PI3K inhibitor LY294002 in C2C12 myotubes. Conclusions: AZL attenuates Ang II-induced skeletal muscle atrophy through AT1R blockade and subsequent activation of PI3K/Akt/FOXO3a signaling, thereby suppressing ubiquitin-proteasome system-mediated muscle protein degradation. These findings provide mechanistic and translational evidence supporting the potential of AZL as a therapeutic strategy for preserving skeletal muscle health in older adults with hypertension.