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

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. We use an irisin knockout mouse to eliminate irisin and pharmacological approaches in a mouse hemorrhagic model to determine the function of irisin on hemorrhage and resuscitation (H/R). Hemorrhage was induced by achieving a mean arterial blood pressure of 35-45 mmHg for 60 min, followed by 2 h of resuscitation in mice. Experimental groups were divided as follows (<i>n</i> = 6-8 per group): sham <i>groups I</i> and <i>II</i>: wild-type (WT) mice and irisin-knockout (KO) mice were subjected to femoral catheterization without H/R; <i>groups III</i> and <i>IV:</i> WT mice and irisin-KO mice were subjected to H/R, respectively; <i>groups V</i> and <i>VI</i>: irisin (50 μg/kg, iv) was infused into WT and irisin-KO H<i>/</i>R mice during resuscitation. Mean blood pressure, myocardial function, serum cytokine, inflammatory cell infiltration, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptosis, active caspase 3, components of oxidative phosphorylation, and mitochondrial ATPase activity in muscles were determined. Irisin deficiency exacerbated cardiac dysfunction in H/R in association with increases in interleukin 6, the infiltration of inflammatory cells, active caspase-3, and reduced oxidative phosphorylation and ATPase activities. The effects of irisin deletion on H/R were rescued by irisin. 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.<b>NEW & NOTEWORTHY</b> Deletion of irisin resulted in a reduction in cardiac function and hemodynamics and exacerbated inflammation and tissue injury in response to hemorrhagic injury. Irisin rescued the hemorrhage-induced cardiac depression and attenuated the inflammatory response induced by irisin deficiency in hemorrhagic injury, suggesting that irisin contributes critically to the protective role in hemorrhage/resuscitation.