Irisin deficiency exacerbates diet-induced insulin resistance and cardiac dysfunction and promotes ischemia and reperfusion injury

The myokine irisin is involved in the regulation of a variety of physiological conditions, metabolism, and survival. We and others have demonstrated that recombinant irisin contributes critically to modulation of insulin resistance and cardiac function. However, the molecular mechanisms by which irisin exerts its physiological effects on cardiac function and insulin sensitivity remain unclear. We utilized the CRISPR/Cas9 genome editing system to delete irisin. Irisin deficiency did not result in abnormalities in development, growth, or cardiac function; however, gene expression profiling showed that several key signaling pathways related to growth, insulin signaling, and integrin signaling were coordinately downregulated. However, loss of irisin resulted in more severe insulin resistance and metabolic derangement when mice were exposed to a high fat diet, which was associated with profound cardiac dysfunction and hypertrophic remodeling. In addition, the loss of irisin also exacerbated myocardial ischemia-reperfusion injury, as indicated by a reduction of post-ischemic ventricular function and an increase in infarct size. Taken together, our results indicate that loss of irisin exacerbates insulin resistance and cardiac depression in response to high fat diet and promotes myocardial ischemia-reperfusion injury. This evidence suggests a role for irisin in modulating insulin resistance, cardiac function and ischemic injury. Cardiomyocytes were obtained from wild type and irisin knockout animals and gene expression was profiled using Affymetrix microarrays.