AAV-mediated expression of IFN-γ induced pronounced cardiac metabolic reprogramming with reduced mitochondrial oxygen consumption and a shift toward glycolysis.
Does elevated systemic IFN-γ induce cardiac metabolic reprogramming in mice?
Interferon-γ (IFN-γ) plays a central role in regulating myocardial inflammation and fibrosis and is relevant across different disease contexts, including ischemic and non-ischemic heart failure. However, the direct effects of IFN-γ on cardiomyocytes remain poorly understood. The aim of this study was therefore to characterize the influence of IFN-γ on cardiac metabolism and subsequent heart function using a novel in vivo model without concomitant myocardial disease or other confounding factors. To this end, male C57BL/6J mice were intravenously injected with a hepatotropic adeno-associated virus (AAV2/8) expressing Ifng and nLuc reporter under the control of the albumin promoter (AAV-Ifng) or with a control virus (AAV-ctrl). On day 28, comprehensive analyses of cardiac changes were performed, including flow cytometry, bulk RNA sequencing, targeted metabolomics, measurements of isolated mitochondrial activity, echocardiography, and in vivo imaging with \ (^18\) Ffluorodeoxyglucose and \ (^18\) Ffluoro-6-thia-heptadecanoic acid. In addition, mice with a cardiomyocyte-specific knockout of the IFN-γ receptor (Myh6\ (^Cre\) Ifngr1\ (^fl/fl\) ) were analyzed to investigate cell-intrinsic effects of IFN-γ signaling on the metabolic reprogramming of cardiomyocytes. After confirming liver-specific transfection and physiologically elevated serum levels of IFN-γ, AAV-Ifng–treated animals displayed pronounced metabolic reprogramming of the heart. RNA sequencing identified a significant IFN-γ response signature accompanied by downregulation of oxidative phosphorylation and fatty acid oxidation. Functional analyses revealed reduced mitochondrial oxygen consumption, while metabolomics confirmed a shift toward glycolysis. These findings were supported by in vivo PET imaging, which demonstrated increased cardiac glucose uptake following AAV-Ifng treatment. These changes were absent in the Myh6\ (^Cre\) Ifngr1\ (^fl/fl\) model, underscoring the direct role of the cardiomyocyte IFN-γ receptor in mediating the observed reprogramming. These results indicate that IFN-γ, beyond its classical role in inflammation, acts as a central regulator of cardiac metabolism, thereby providing new potential mechanistic insights into immunological control of heart failure.
Ebram Melika (2026) studied Cardiac metabolic reprogramming. AAV-Ifng (Interferon-gamma expression) vs. AAV-ctrl (control virus) was evaluated on Cardiac metabolic reprogramming. AAV-mediated expression of IFN-γ induced pronounced cardiac metabolic reprogramming with reduced mitochondrial oxygen consumption and a shift toward glycolysis.