A novel repurposing opportunity for valsartan: angiotensin II type 1 receptor blockade dampens muscle-to-brain sensitization in fibromyalgia by targeting lncRNA H19/miR-29a-3p, inflammatory mediators, AKT/CREB signaling, neurotrophic factors, and amy

Fibromyalgia (FM) is a debilitating nociplastic pain disorder increasingly recognized to involve skeletal muscle as an active contributor to peripheral nociception and central sensitization rather than a passive target of disease. Although angiotensin II promotes pain signaling through angiotensin type-1 (AT 1 ) receptor activation, the role of skeletal muscle AT 1 receptor signaling in orchestrating the inflammatory, trophic, and proteotoxic disturbances underlying FM remains unexplored. This study investigated, for the first time, whether AT 1 receptor blockade by valsartan interrupts maladaptive muscle-derived signals that drive FM-associated pain and fatigue. Female rats were allocated into control groups (vehicle- and valsartan-treated) and reserpine-induced FM groups that either received oral valsartan for six consecutive days or remained untreated. Valsartan alleviated mechanical allodynia and hyperalgesia while enhancing motor performance and fatigue resistance. Mechanistically, FM muscle exhibited upregulation of lncRNA H19 accompanied by suppression of miR-29a-3p, fostering a pro-inflammatory milieu characterized by increased IL-6, CX3CL1, and IL-1β. These alterations coincided with activation of the AKT/CREB pathway, increased inhibitory phosphorylation of GSK3β, accumulation of Aβ1–42 and p-Tau, and diminished trophic support, evidenced by reduced IGF-1, BDNF, and p-TrkB. Notably, valsartan reversed these pathological cascades by suppressing lncRNA H19, restoring miR-29a-3p, attenuating IL-6 and CX3CL1, modulating AKT/CREB & GK3β signaling, reducing Aβ1–42 and p-Tau levels, and enhancing IGF-1, BDNF, and p-TrkB expression. Altogether, the present findings position skeletal muscle as an active orchestrator of FM pathology and highlight AT 1 receptor blockade as a promising strategy to interrupt the muscle-to-brain signaling network that sustains chronic pain, fatigue, and impaired muscle performance.