bims-hafaim 2025-09-21 papers

Issue of 2025–09–21
four papers selected by
Kyle McCommis, Saint Louis University

bioRxiv. 2025 Sep 07. pii: 2025.08.31.673391. [Epub ahead of print]

Interferon gamma signaling drives cardiac metabolic rewiring.

Ebram Tharwat Melika, DiyaaElDin Ashour, Kyoungmin Kim, Alexander Nickel, Paula Arias-Loza, Xinyu Chen, Panagiota Arampatzi, Mugdha Srivastava, Martin Väth, Edécio Cunha, Michaela Kuhn, Georg Gasteiger, Ulrich Hofmann, Takahiro Higuchi, Christoph Maack, Stefan Frantz, Anja Karlstaedt, Gustavo Campos Ramos.

Background: IFN-gamma (IFN-γ) signaling influences myocardial inflammation and fibrosis across a wide range of conditions, including ischemic and non-ischemic heart failure (HF). However, the direct effects of IFN-γ on cardiomyocytes remain poorly understood. Here, we developed a novel in vivo model to investigate how IFN-γ impacts myocardial metabolism and function.
Methods: Male C57BL/6J mice were injected intravenously with hepatotropic adeno-associated virus (AAV2/8) carrying Ifng and nLuc reporter under the albumin promoter (AAV-Ifng) or empty vector control virus (AAV-ctrl). Cardiac alterations were monitored on day 28 through flow cytometry, bulk RNA sequencing, targeted metabolomics, isolated mitochondrial activity, echocardiography, and in vivo imaging using [18F]fluordeoxyglucose ([18F]FDG) and [18F]fluoro-6-thia-heptadecanoic acid. Additionally, mice lacking IFN-γ receptor expression in cardiomyocytes (Myh6 Cre Ifngr1 fl/fl) were used to further dissect the cell-intrinsic roles of IFN-γ signaling in cardiomyocyte metabolic reprograming.
Results: After confirming liver-specific viral transfection and elevated serum IFN-γ production at physiological levels, we observed cardiac metabolic adaptation and rewiring in animals treated with AAV-Ifng compared to control animals. Myocardial bulk RNA sequencing and gene set enrichment analysis identified an IFN-γ response signature accompanied by marked down-regulations of oxidative phosphorylation and fatty acid oxidation pathways. Functional assessment of isolated cardiac mitochondria showed decreased oxygen consumption, and targeted metabolomics confirmed metabolic shifts toward glycolysis in mice overexpressing IFN-γ. In vivo imaging confirmed increased cardiac glucose uptake following AAV-Ifng treatment. Notably, these metabolic alterations were abrogated in mice with cardiomyocyte-specific deletion of IFN-γ receptors (IFNGR).
Conclusions: Systemic IFN-γ induces pronounced metabolic reprogramming in the heart, characterized by increased glucose uptake and reduced oxidative phosphorylation, via direct signaling through cardiomyocyte IFNGR. These alterations mirror those observed in aging and some forms of HF, thereby highlighting that, beyond classical inflammation, this cytokine regulates cardiac metabolism.

Keywords: T cells; cardiac metabolism; cardiomyocytes; interferon gamma; mitochondria

DOI: https://doi.org/10.1101/2025.08.31.673391

Am J Physiol Heart Circ Physiol. 2025 Sep 15.

Metabolic Modulation of Pyruvate Dehydrogenase and Glucose Oxidationin Diabetic Cardiomyopathy: Pathways, Perspectives, and Potentials.

Jordan S F Chan, Linyue Dong, John R Ussher.

Individuals living with obesity and/or type 2 diabetes (T2D) are at a disproportionately high risk of developing cardiovascular disease. This includes diabetic cardiomyopathy (DbCM), a condition characterized by left ventricular diastolic dysfunction that is often present in individuals with pre- or early-stage T2D. Although there are numerous mediators that contribute to the development of DbCM, perturbations in cardiac substrate metabolism are widely believed to play a major role in its pathogenesis. In particular, myocardial glucose oxidation is often suppressed due to decreased activity of the pyruvate dehydrogenase (PDH) complex, the rate-limiting enzyme of glucose oxidation, which is responsible for decarboxylating pyruvate to acetyl CoA, thus acting as the link between glycolysis and oxidative phosphorylation of glucose. Importantly, numerous preclinical studies suggest that restoring suppressed myocardial glucose oxidation can alleviate DbCM. In this review we will describe the major perturbations that characterize myocardial substrate metabolism is T2D, while discussing the primary pharmacological approaches that have been pursued to stimulate myocardial PDH activity and glucose oxidation. We will also highlight potential mechanisms explaining how increasing myocardial PDH activity and glucose oxidation favorably influence diastolic function. Given the increasing prevalence of DbCM in the human population, it is not only imperative to better understand its pathophysiology but to also develop novel therapies for its management, which may also have utility in the management of heart failure with preserved ejection fraction.

Keywords: diabetic cardiomyopathy; glucose oxidation; pyruvate dehydrogenase; substrate metabolism; type 2 diabetes

DOI: https://doi.org/10.1152/ajpheart.00063.2025

ESC Heart Fail. 2025 Sep 19.

SGLT2 inhibitors for the prevention and treatment of heart failure: A scientific statement of the HFA and the HFAI.

In the 2021 European Society of Cardiology (ESC) heart failure (HF) guidelines, sodium-glucose cotransporter 2 (SGLT2) inhibitors were recommended for the prevention of HF in patients with type 2 diabetes mellitus (T2DM) and for the treatment of HF with reduced ejection fraction (HFrEF). Further trials showed efficacy of empagliflozin and dapagliflozin in patients with HF with preserved ejection fraction (HFpEF). These results prompted a broadened recommendation for the SGLT2 inhibitors dapagliflozin or empagliflozin across the whole left ventricular ejection fraction (LVEF) spectrum in the 2023 Focused Update of the ESC HF guidelines and in other international guidelines. In SOLOIST-WHF and EMPULSE, sotagliflozin (enrolling only patients with T2DM) and empagliflozin, respectively, were beneficial when initiated at the end or soon after an episode of decompensated HF. Based on these results and on the early appearance of their beneficial effects, the administration of SGLT2 inhibitors should start early in patients hospitalized for acute HF. Analyses after study drug withdrawal in randomized clinical trials have shown that their benefits may decline rapidly after discontinuation, and thus, persistence of treatment is advised. In EMPACT-MI, empagliflozin did not reduce the primary outcome of cardiovascular (CV) death/HF hospitalization but reduced first/recurrent HF hospitalizations. Potential benefits of SGLT2 inhibitors in further specific conditions (i.e., cardiac amyloidosis, grown-up congenital heart disease and paediatric patients with HF) have been reported in observational studies but need confirmation from prospective trials. This scientific statement summarizes current evidence regarding the effects of SGLT2 inhibitors for the prevention and treatment of HF.

Keywords: GDMT; SGLT2 inhibitors; heart failure; prevention; treatment

DOI: https://doi.org/10.1002/ehf2.15408

FASEB Bioadv. 2025 Sep;7(9): e70049

GCN5L1 Inhibits Pyruvate Dehydrogenase Phosphorylation During Cardiac Ischemia-Reperfusion Injury.

Paramesha Bugga, Michael W Stoner, Janet R Manning, Bellina A S Mushala, Nisha Bhattarai, Maryam Sharifi-Sanjani, Iain Scott.

Myocardial infarction remains one of the leading causes of mortality. Reperfusion of the infarcted myocardium restores blood flow and reduces primary ischemic injury. However, despite its protective function, reperfusion is also associated with several deleterious outcomes that can result in ischemia-reperfusion (I/R) injury to cardiac tissue. Although negative outcomes such as reactive oxygen species generation are strongly associated with I/R injury, cardiac energy metabolism is also greatly disrupted. Furthermore, previous studies have shown that the restoration of normal fuel oxidation in the myocardium regulates the extent of contractile recovery. A better understanding of the pathophysiological mechanisms underlying I/R injury may allow us to develop new treatments that limit the negative aspects of the process. In this study, we examined the role played by GCN5L1, a protein implicated in the regulation of energy metabolism, in I/R injury. We demonstrate that cardiac-specific loss of GCN5L1 promotes the inhibitory phosphorylation of pyruvate dehydrogenase in vitro and in vivo, a process likely to inhibit glucose oxidation, and that this corresponds to increased myocardial damage following ischemia-reperfusion (I/R) injury.

Keywords: GCN5L1; PDH; glucose; glycolysis; ischemia

DOI: https://doi.org/10.1096/fba.2025-00187