Irisin Preserves Cardiac Performance and Insulin Sensitivity in Response to Hemorrhage

Abstract

Irisin, a cleaved product of the fibronectin type III domain containing protein-5, is produced in the muscle tissue, which plays an important role in modulating insulin resistance. However, it remains unknown if irisin provides a protective effect against the detrimental outcomes of hemorrhage. Hemorrhages were simulated in male CD-1 mice to achieve a mean arterial blood pressure of 35–45 mmHg, followed by resuscitation. Irisin (50 ng/kg) and the vehicle (saline) were administrated at the start of resuscitation. Cardiac function was assessed by echocardiography, and hemodynamics were measured through femoral artery catheterization. A glucose tolerance test was used to evaluate insulin sensitivity. An enzyme-linked immunosorbent assay was performed to detect inflammatory factors in the muscles and blood serum. Western blot was carried out to assess the irisin production in skeletal muscles. Histological analyses were used to determine tissue damage and active-caspase 3 apoptotic signals. The hemorrhage suppressed cardiac performance, as indicated by a reduced ejection fraction and fractional shortening, which was accompanied by enhanced insulin resistance and hyperinsulinemia. Furthermore, the hemorrhage resulted in a marked decrease in irisin and an increase in the production of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). Additionally, the hemorrhage caused marked edema, inflammatory cell infiltration and active-caspase 3 positive signals in skeletal muscles and cardiac muscles. Irisin treatment led to a significant improvement in the cardiac function of animals exposed to a hemorrhage. In addition, irisin treatment improved insulin sensitivity, which is consistent with the suppressed inflammatory cytokine secretion elicited by hemorrhages. Furthermore, hemorrhage-induced tissue edema, inflammatory cell infiltration, and active-caspase 3 positive signaling were attenuated by irisin treatment. The results suggest that irisin protects against damage from a hemorrhage through the modulation of insulin sensitivity.

Inhibition of integrin alpha v/beta 5 mitigates the protective effect induced by irisin in hemorrhage

“…Using sharp scissors, a 2 cm long straight incision was made starting immediately from the medial thigh towards the knee to fully expose the area overlying the femoral artery. The femoral nerve, artery and vein were isolated from the connective tissue using arterial forceps as previous described ( Kulthinee et al, 2022 ). The right and left femoral arteries were inserted with PE-10 fused to PE-50 tubes containing heparinized saline.…”

“…Hemorrhage induction was carried out according to the previously established protocol ( Kulthinee et al, 2022 ). In brief, hemorrhage was induced by removing blood from the right femoral artery until MAP reached 35–45 mmHg.…”

“…Irisin has been found to have anti-inflammatory and antioxidant effects which may help reduce the extent of tissue damage caused by hemorrhage ( Li et al, 2021c ; Slate-Romano et al, 2022 ; Zhu et al, 2021 ). Our previous study demonstrated a significant reduction in the amount of irisin in mice exposed to hemorrhage, and that the treatment of these mice with irisin resulted in improved insulin resistance ( Kulthinee et al, 2022 ).…”