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 AZL treatment was associated with significant improvements in handgrip strength, gait speed, and appendicular skeletal muscle mass in older hypertensive patients. In experimental models, Ang II induced skeletal muscle dysfunction and atrophy, characterized by reduced exercise capacity, decreased grip strength, and muscle fiber loss, were attenuated by AZL treatment. Mechanistically, AZL restored PI3K/Akt/FOXO3a signaling and suppressed the expression of the muscle-specific ubiquitin ligases Atrogin-1 and MuRF1. The protective effects of AZL were abolished by the AT1R agonist TRV120027 in both in vivo and in vitro 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.
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