Irisin regulates cardiac myocyte energy metabolic remodeling involved the ADRA1A-AMPK signaling pathwayng pathway

In this study, we established a hypoxia-induced cardiac cell injury model using HL-1 cardiomyocytes and investigated the effects of Irisin intervention on the preventive and therapeutic effects of Irisin on chronic heart failure (CHF), and the underlying mechanisms in a murine model.

Initially, we explored the concentration of Irisin in untreated and hypoxia-induced HL-1 cells, ultimately determining the optimal concentration to be 20 ng/ml. To investigate the impact and underlying mechanisms of Irisin on substrate selection in hypoxic (Hx) cardiac myocytes, we performed a series of assays, including quantitative PCR, western blot analysis, mitochondrial membrane potential measurement, and ATP production assessment. Furthermore, we established a murine model of CHF induced by aortic constriction and assessed the effects of Irisin on cardiac energy metabolism and the prevention and treatment of HF using methods such as cardiac ultrasound, tissue ATP generation measurement, transmission electron microscopy, HE staining, and TUNEL staining.

Irisin concentrations below 20 ng/mL enhanced HL-1 cell viability under hypoxia in a dose-dependent manner. Irisin administration counteracted hypoxia-induced reductions in the mitochondrial membrane potential and ATP production, with these protective effects diminished by Compound C. Hypoxia-mediated suppression of genes crucial to energy metabolism, such as PGC-1, MCP1, GLUT4, and CPT-1, was effectively countered by Irisin. Moreover, Irisin was found to regulate energy metabolism in Hx cardiomyocytes via the ADRA1A-AMPK pathway. In the CHF mouse model, Irisin significantly improved cardiac function and energy metabolism.

Irisin showcases substantial therapeutic potential against hypoxia-induced cardiomyocyte damage, acting predominantly through the AMPK signaling pathway. Its efficacy in enhancing cardiac function and energy metabolism in vivo further underscores its promise as a prospective treatment for cardiac conditions characterized by hypoxia.