Abstract P2144: Irisin, An Exercise-induced Myokine, Exhibits Protective Effects In Glucocorticoid-induced Cardiac Muscle Dysfunctions

Abstract

Myocardial infarction caused by pharmacological substances, such as anti-inflammatory drugs, is a serious adverse drug effect in the cardiovascular system that often causes heart failure. Dexamethasone (DEX), a synthetic glucocorticoid, is commonly used as potent anti-inflammatory and immunosuppressive drugs, but is classified as one of the prime suspects of drug-induced acute myocardial infarction. High dose of DEX increased oxidative stress of the heart, induced myocardial degeneration and cardiomyocyte apoptosis and impaired cardiac contraction. Thus, therapeutic approaches are required to alleviate glucocorticoids-induced cardiotoxicity and prevent DEX-mediated cardiac complications. Exercise-induced secretion of irisin showed the beneficial effects against cardiovascular diseases on energy metabolism, anti-oxidant effects, and decreased inflammation and apoptosis by promoting mitochondria biogenesis, decreasing oxidative stress and inflammatory responses, and regulating intracellular calcium signaling. In this study, we investigate the endocrine effects of muscle-secreted irisin against DEX-induced cardiotoxicity. We engineered anisotropic human induced-pluripotent stem cell-derived cardiomyocyte tissues and designed three experimental groups: control, dex treatment, and dex plus irisin treatment. We then analyze the tissues with qPCR, immunostaining (muscle atrophy markers), contractility assay, and oxygen consumption assay to evaluate the protective effects of irisin on DEX-induced cardiac injury. Injured cardiac tissues showed systolic dysfunction by decreasing oxygen consumption, increasing muscle atrophy marker (MuRF-1), and significantly reducing systolic contractile force, but not diastolic stress. In contrast, these DEX-induced maladaptive responses was alleviated by irisin pretreatment by reducing proteolytic activity and muscle atrophy signaling pathways and promoting mitochondria biogenesis. In conclusion, our micro-physiological system showed the therapeutic effects of irisin against DEX-induced cardiotoxicity.