Piezo1 Responsiveness in Muscle Afferents and Mechanoreflex in Diabetic Rats

BACKGROUND: Abnormal mechanoreflex function from skeletal muscle significantly contributes to the heightened circulatory response during exercise in type 2 diabetes (T2DM). However, the underlying mechanisms remain unclear. We hypothesized that the abnormal cardiovascular responses in T2DM are mediated by mechanoreflex-induced exaggerations resulting from enhanced Piezo1-mediated mechanosensitivity of muscle afferents. METHODS: T2DM rats (Sprague-Dawley rats) were given a high-fat diet in combination with a low dose of streptozotocin. Using an in vivo decerebrated rat model and an ex vivo single-fiber recording preparation, we measured muscle mechanoreflex responses, mechanosensitivity of muscle afferents, and Piezo1-mediated responses. Piezo1 protein levels in the membrane fraction were detected by Western blotting in human embryonic kidney 293 (HEK293) cells. RESULTS: Blood pressure and sympathetic nerve activity responses to mechanoreflex activation, as well as group IV muscle afferent firing to mechanical stimulation and the Piezo1 agonist (Yoda1), were significantly greater in T2DM rats. More importantly, Piezo1 agonist-induced blood pressure changes and group IV afferent firing were significantly potentiated by administration of lipopolysaccharide, a gut-derived inflammatory endotoxin. Furthermore, lipopolysaccharide significantly increased Piezo1 protein in the cell membrane, which was attenuated by a PKA (protein kinase A) inhibitor. CONCLUSIONS: These findings suggest that activation of the lipopolysaccharide-Piezo1 pathway may contribute to enhanced responsiveness of group IV muscle afferents and may be associated with exaggerated circulatory responses to muscle mechanoreflex activation in T2DM.