bims-hafaim 2025-12-28 papers

Issue of 2025–12–28
five papers selected by
Kyle McCommis, Saint Louis University

J Pharm Pharm Sci. 2025 ;28 15688

Pharmacological increases in circulating ketones fail to alleviate the hypertrophic cardiomyopathy present in the Tafazzin knockdown mouse model of Barth syndrome.

Tanin Shafaati, Amanda A Greenwell, Christina T Saed, Seyed Amirhossein Tabatabaei Dakhili, Jordan S F Chan, Linyue Dong, Magnus J Stenlund, Sally R Ferrari, Ruth Han, Jennifer Kruger, Farah Eaton, Keshav Gopal, Sandra T Davidge, Gavin Y Oudit, John R Ussher.

Objective: Mutations in the tafazzin gene lead to impaired remodeling of cardiolipin, thereby impairing mitochondrial function and causing Barth syndrome (BTHS), a rare X-linked genetic disorder characterized by cardiomyopathy. Previous studies in a mouse model of BTHS, secondary to knockdown of Tafazzin (TazKD mice), also observed perturbations in mitochondrial substrate metabolism and a hypertrophic cardiomyopathy. BTHS may be characterized by increased cardiac ketone metabolism, as myocardial protein expression of the ketolytic enzyme, β-hydroxybutyrate dehydrogenase 1 (BDH1), was markedly increased in TazKD mice. We therefore determined whether increasing ketone supply in TazKD mice may have therapeutic utility against their cardiac abnormalities.
Methods: We treated TazKD mice and their wild-type littermates with either the sodium-glucose cotransporter-2 inhibitor, empagliflozin (10 mg/kg), or a ketone ester (KE; 1719 mg/kg) once daily for 7-week, and performed ultrasound echocardiography to assess cardiac structure and function.
Results: Treatment of TazKD mice with either empagliflozin or a KE increased circulating ketone levels. However, neither approach proved capable of alleviating the cardiac hypertrophy present in TazKD mice, as their increased left ventricular wall thickness and decreased left ventricular diameter remained comparable to that observed in vehicle control treated animals. We also observed that empagliflozin and KE treatment did not impact key markers of cardiac hypertrophy in TazKD mice.
Conclusion: Increasing circulating ketone levels did not alleviate the cardiac hypertrophy in TazKD mice, suggesting that such an approach would not improve outcomes in BTHS.

Keywords: Barth syndrome; cardiomyopathy; empagliflozin; ketones; substrate metabolism

DOI: https://doi.org/10.3389/jpps.2025.15688

Nan Fang Yi Ke Da Xue Xue Bao. 2025 Dec 20. pii: 1673-4254(2025)12-2598-09. [Epub ahead of print]45(12): 2598-2606

[Overwork damages myocardial energy metabolism homeostasis in mice].

Junjie Cui, Ruiyin Lai, Suheng Chen, Shanshan Qu, Yue Liao, Xue Ma, Yulan Li.

OBJECTIVES: To investigate the effect of overwork on myocardial energy metabolism in mice.
METHODS: Thirty-two C57BL/6J mice were randomized equally into a control group and 3 overwork groups with overwork for 2, 4, and 6 weeks (W2, W4, and W6 groups, respectively). The mice in overwork groups were subjected to daily forced water standing and restraint. The changes in body weight and general condition of the mice were observed weekly. After successful modeling, the mice were examined for changes in echocardiography, blood glucose/lipid profiles, myocardial pathologies, myocardial TG and ATP levels, and expressions in CD36, GLUT1, CPT1B, PPARα, PFKM, and PKM2 using immunohistochemistry, RT-qPCR or Western blotting.
RESULTS: The mice with prolonged overwork exhibited reduced activity with hair loss, dull fur, and slowed body weight gain without significant changes in cardiac index or function. Blood glucose levels increased significantly in W2 and W4 groups but decreased in W6 group. Serum TG level increased significantly while TC, HDL, and LDL decreased in W4 and W6 groups. HE staining revealed myocardial swelling, disorganization, and vacuolation in the mouse models. Myocardial TG was elevated in W4 and W6 groups and ATP level decreased in W6 group. The mRNA and protein expressions of CPT1B and PPARα were downregulated in W4 and W6 group, and CD36 expression increased significantly in W4 group. GLUT1 and PFKM/PKM2 expressions decreased obviously in W2 group but increased in W4 and W6 group compared with that in W2 group.
CONCLUSIONS: Short-term overwork causes elevation of blood glucose and suppresses glycolysis in mice, while prolonged overwork reduces glucose, increases TG, impairs fatty acid oxidation, and limits glycolytic compensation to eventually result in myocardial damage, lipid accumulation, and ATP deficiency.

Keywords: energy metabolism; fatty acid oxidation; glycolysis; myocardium; overwork

DOI: https://doi.org/10.12122/j.issn.1673-4254.2025.12.07

Curr Probl Cardiol. 2025 Dec 18. pii: S0146-2806(25)00274-9. [Epub ahead of print] 103255

The Early Initiation of Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Decompensated Heart Failure: A Systematic Review and Meta-analysis.

Ahmad Al-Abdouh, Ahmad Jabri, Mohammed Mhanna, Laith Alhuneafat, Fares Ghanem, Ibrahim Mortada, Omar Obeidat, Shareef Mansour, Wissam Khalife.

INTRODUCTION: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown significant reduction in cardiovascular mortality and heart failure hospitalization in patients with chronic heart failure. Despite their benefits in chronic heart failure, their use during episodes of acute decompensation remains under investigation.
METHODS: A comprehensive literature search was performed using PubMed, Google Scholar, and ClinicalTrials.gov from database inception through September 3, 2025. The predefined endpoints were all-cause mortality, heart failure hospitalizations, and a composite of cardiovascular mortality or heart failure worsening. Outcomes were pooled using a random effects Mantel-Haenszel model. The DerSimonian and Laird method was used for estimation of τ2. We reported effect sizes as risk ratios (RR) with 95% confidence interval (CI).
RESULTS: A total of eight randomized controlled trials, encompassing 4,714 patients, were included in the analysis. Among patients hospitalized with decompensated heart failure, treatment with SGLT2 inhibitors compared with standard care only (control group) was associated with a significant decrease in all-cause mortality (RR 0.72; 95% CI, 0.58-0.90; P < 0.01; I² = 0%), and in the composite outcome of cardiovascular mortality or heart failure rehospitalization (RR 0.68; 95% CI, 0.53-0.86; P < 0.01; I² = 28%). However, no significant reduction was observed in heart failure rehospitalization as an isolated outcome (RR 0.92; 95% CI, 0.82-1.03; P = 0.16; I² = 0%).
CONCLUSION: SGLT-2 inhibitors during hospitalization for acute decompensated heart failure is effective and led to decrease in all-cause mortality and a composite endpoint of cardiovascular mortality or heart failure hospitalizations.

Keywords: SGLT-2 inhibitors; decompensated heart failure

DOI: https://doi.org/10.1016/j.cpcardiol.2025.103255

bioRxiv. 2025 Dec 18. pii: 2025.12.15.694522. [Epub ahead of print]

Multiomics Integration Reveals a Metabolic Myopathy in Cardiometabolic HFpEF.

Timothy D Allerton, Daniel Arabie, Kade Malone, Abhishek Pandit, Mahmoud H Elbatreek, Zhen Li, Robert C Noland, Jake Doiron, Mike Kinter, Brooke Loveland, Pravalika Javvadi, Kirti Agrawal, Manas Gartia, Praveen Guttula, Traci T Goodchild, Sanjiv J Shah, Sujoy Ghosh, David J Lefer.

Background: Skeletal muscle dysfunction is a major peripheral determinant of exercise intolerance and physical disability in heart failure with preserved ejection fraction (HFpEF). Metabolic and mitochondrial dysfunction are considered to be key components of skeletal muscle dysfunction, but comprehensive profiling of metabolic pathways has not been conducted. Elucidation of dysregulated metabolic pathways is essential to determine viable targets for the treatment of exercise intolerance in HFpEF.
Methods: Male ZSF1 Obese rats (HFpEF) and Wistar Kyoto (WKY) lean normotensive controls were studied at 26 weeks of age. Gastrocnemius was subjected to bulk RNA-seq, proteomics, metabolomics, and lipidomics analysis. The R package limma was used to determine differential expression in all omics layers (absolute fold-change>1.5, FDR0.05, unless otherwise indicated). Additional targeted plasma and skeletal muscle (soleus and EDL) metabolomics and lipidomics were performed on HFpEF and control rats.
Results: Pathway level analysis for RNA seq and proteomics revealed significant downregulation of oxidative phosphorylation (NES -2.1, p<0.005), electron transport chain (NES -2.0, p<0.005), and TCA cycle (-1.8, p<0.05). The most upregulated pathways were PPAR signaling (NES 2.2, p<0.0001), tryptophan metabolism (NES 1.8, P<0.005), and amino acid oxidation (NES 1.8, p<0.005) pathways. Metabolomics revealed an accumulation of TCA cycle intermediate, isocitrate, and phosphate reduction. Branched-chain amino acids were significantly increased, whereas amino acids related to tryptophan metabolism were reduced and shifted towards increased serotonin accumulation. Phospholipid species were differentially regulated with increased palmitoylated phosphatidylcholines but reduced arachidonoyl-PC species. Phosphatidylethanolamines (PE) species (16:0/16:1-18:0/18:2) were increased.
Conclusion: Our multiomics analysis of skeletal muscle in HFpEF revealed severe mitochondrial dysfunction that was characterized by reduced complex I and II activity. Mitochondrial and peroxisomal lipid overload results in a shift in membrane phospholipid accumulation and composition. Reduced BCAA oxidation and dysregulation of tryptophan metabolism are key features of amino acid metabolism that reduce anaplerosis and promote the accumulation of toxic metabolites. Comparative analysis of other skeletal muscle disorders suggests that an acquired metabolic myopathy exists in cardiometabolic HFpEF.

DOI: https://doi.org/10.64898/2025.12.15.694522

Genes Dis. 2026 Mar;13(2): 101784

cTnIR193H restrictive cardiomyopathy mice satisfy high-energy metabolic demands through regulating glucose metabolism.

Min Luo, Lingjuan Liu, Wenjing Yuan, Junjun Quan, Mi Li, Jie Tian.

This work aims to investigate the energy metabolism in mice with restrictive cardiomyopathy induced by cardiac troponin I (cTnI) R193H mutation. Echocardiography was used to monitor cardiac function. ATP content and ATPase activity were detected with relevant kits. The expression levels of GLUT4, FAT/CD36, and PI3K/AKT pathway proteins were detected. Proteomics and phosphorylation omics were used to analyze the differential expression and modification of cardiac proteins and related pathways, respectively. The utilization of cardiac energy substrates was investigated using relevant kits. The isovolumic relaxation time of 4-month-old cTnI193His-M mice was significantly prolonged (P < 0.01); Cardiac ATP content, ATPase activity, and mitochondrial number were significantly increased (P < 0.05, P < 0.01, and P < 0.01, respectively); GLUT4 expression level increased (P < 0.01); the expression level of CD36 decreased (P < 0.01). Proteomic results showed that the glycolytic/gluconeogenic pathway was up-regulated. Phosphorylation omics was enriched in the inositol phosphate metabolism pathway and PI3K/AKT pathway. In conclusion, at the early stage of diastolic dysfunction, cTnI193His-M mice may increase glucose uptake and metabolism through the PI3K/AKT pathway to satisfy the high energy demand, which may contribute to the development of myocardial fibrosis and heart failure.

Keywords: Glucose and fatty acid intake; Glucose metabolism; PI3K/Akt; Restrictive cardiomyopathy; cTnIR193H mutation

DOI: https://doi.org/10.1016/j.gendis.2025.101784