Oestrogen-related receptor γ in sepsis-induced cardiomyopathy: role of cardiomyocyte subtype conversion

Abstract Background and Aims Sepsis remains one of the leading causes of death worldwide, and sepsis-induced cardiomyopathy (SICM) increases the overall mortality rate of sepsis patients. Currently, targeting therapies for SICM are lacking, due to the incomplete understanding of the pathophysiological mechanisms of SICM. Current research on the mechanisms of SICM remains at the level of the whole heart, lacking detailed studies at the single-cell levels. Methods Transcriptomic dynamics of cardiomyocytes and non-cardiomyocytes were examined in mice with caecal ligation and puncture (CLP)-induced sepsis model using single-nucleus RNA sequencing (snRNA-seq). Cultured neonatal rat ventricular myocytes, human embryonic stem cell-derived cardiomyocytes, and adult rat and human ventricular myocytes, and in vivo mouse models with myocardial injury induced by CLP (or lipopolysaccharide), were used to investigate the mechanisms of SICM. The findings of cardiomyocyte subtype conversion and its regulatory mechanisms were validated using human hearts. Results snRNA-seq analysis revealed that in normal hearts, cardiomyocytes were primarily divided into three major types: contractile cardiomyocytes, injury-responsive cardiomyocytes, and transitional cardiomyocytes. In both cultured cells (including neonatal rat ventricular myocytes, human embryonic stem cell-derived cardiomyocytes, adult rat ventricular myocytes, and adult human ventricular myocytes) and in vivo mouse model of sepsis, contractile cardiomyocytes converted into the injury-responsive subtype during the early stage of sepsis, which, although reducing myocardial contractility and impairing heart function, prevented sepsis-induced reactive oxygen species production and cell injury in cardiomyocytes. This subtype conversion of cardiomyocytes was driven by the reduction of oestrogen-related receptor γ (ERRγ) in contractile cardiomyocytes. In the CLP mouse model, after the acute phase of infection, ERRγ agonist promoted the conversion of injury-responsive cardiomyocytes back to the contractile type, improving cardiac function and prognosis in SICM. Finally, sepsis-elicited cardiomyocyte subtype conversion was confirmed in human hearts. Conclusions This study not only identifies cardiomyocyte subtype conversions as a key pathophysiological basis for SICM-induced cardiac dysfunction but also establishes ERRγ as the central regulatory mechanism governing these conversions. Activating ERRγ has the potential to ameliorate cardiac dysfunction in SICM. This work provides new insights into the pathophysiology of SICM, offering novel therapeutic strategies for its prevention and treatment.