Irisin deficiency exacerbates cardiac dysfunction and enhances hemorrhage injury in hemorrhage/resuscitation

Background: Irisin contributes critically to modulating metabolism and tissue survival in muscles and adipocytes. Whether deficiency of irisin impacts the hemorrhagic injury and/or whether the effect of irisin deficiency on hemorrhagic injury primarily relies on Irisin, which is currently unknown. Objectives: We utilize irisin knockout mouse to eliminate Irisin and pharmacological approaches in mouse hemorrhagic model to determine the function of Irisin on hemorrhage and resuscitation (H/R). Methods: Hemorrhage was induced by achieving a mean arterial blood pressure of 35-45 mmHg for 60 minutes followed by two hours of resuscitation in mice. Experimental groups were divided as the following (n=6-8/per group): Sham group I and II: Wild type (WT) mice and Irisin-KO mice were subjected to femoral catheterization without H/R; Groups III and IV: WT mice and Irisin-KO mice were subject to H/R, respectively; Groups V and VI: Irisin (50μg/kg, i.v.) was infused into WT and Irisin-KO H/R mice during resuscitation. Mean blood pressure, myocardial function, serum cytokine, inflammatory cell infiltration, and TUNEL positive apoptosis, active caspase 3, components of oxidative phosphorylation and mitochondrial ATPase activity in muscles were determined. Results: Irisin deficiency exacerbated cardiac dysfunction in H/R in association with increases in IL-6, the infiltration of inflammatory cells, active caspase-3 and reduced oxidative phosphorylation OXPHOS) and ATPase activities. The effects of Irisin deletion on H/R was rescued by Irisin. Conclusion: Deletion of Irisin exacerbated injury of H/R, which was rescued by infusion of Irisin, suggesting a key role of Irisin in the regulation of hemorrhage/resuscitation.