Biology subjects

Podesser, B. K.

Publications and source records attributed to Podesser, B. K..

4 recordsLinked to original sources

bioRxiv2026

A novel role for Oxaloacetate Decarboxylase FAHD1 in cardiomyocyte maturation

Mitochondrial metabolism undergoes dramatic reprogramming during postnatal cardiac maturation, yet the enzymatic regulators that ensure continuity of TCA cycle flux in this period remain incompletely defined. FAHD1 is a mitochondrial oxaloacetate decarboxylase (ODx) with proposed roles in modulating the activity of Complex II of the electron transport chain (ETC), but its physiological relevance in vivo has remained unclear. Here, we identify FAHD1 as a critical regulator of mitochondrial function with strong impact on cardiomyocyte (CM) maturation. Using a germline Fahd1-knockout (KO) mouse model, we show that Fahd1 deficiency impairs Complex II respiration, reduces pyruvate levels, and induces a compensatory metabolic shift toward glycolysis and anabolic biosynthesis. Loss of FAHD1 disrupts sarcomere organization, delays the fetal-to-adult myosin isoform switch, and leads to left ventricle systolic dysfunction and cardiomyocyte hypertrophy. These findings highlight FAHD1 as a mitochondrial gatekeeper and potential target for modulating cardiac development and disease.

cell biology↗

bioRxiv2026

Cardiac GLP1R gene Expression: A Cross-Species Single-Cell Transcriptomic Analysis

Glucagon-like peptide-1 receptor (GLP1R) agonists improve glycaemic control, induce weight loss, and consistently reduce major adverse cardiovascular events. However, the mechanistic basis of their cardioprotective effects remains incompletely understood, particularly whether benefits arise solely from systemic actions or also involve direct cardiac GLP1R signalling. To address this, we performed integrated single-cell and single-nucleus transcriptomics to map GLP1R gene expression across human and murine organs, cardiac cell types, disease states, and hiPSC-derived cardiac organoids. In humans, GLP1R expression was predominantly pancreatic, with low cardiac expression largely restricted to cardiomyocytes and consistently upregulated across ischaemic, dilated, and hypertrophic cardiomyopathy. In contrast, murine cardiac Glp1r expression was confined to endocardial cells and remained unchanged in heart disease. Other cardiac cell types, including fibroblasts, endothelial cells, and mural cells, showed minimal GLP1R expression in both species. Human cardiac organoids recapitulated ventricular GLP1R patterns closer to adult human myocardium than murine tissue. Together, these findings indicate that GLP1R is primarily extracardiac but selectively induced in failing human myocardium, supporting a model in which myocardial GLP1R signalling augments systemic mechanisms to confer GLP1R agonist-mediated cardioprotection.

bioinformatics↗

bioRxiv2025

Infarctsize-AI: an efficient infarct size image analysis tool for small rodent myocardial infarction studies

BackgroundMyocardial infarct size (IS) is the gold standard end-point in shorth-term studies on cardioprotection. However, IS quantification in rodent models with standard Evans Blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining is time-consuming and prone to inter-observer variance. Therefore, we aimed to develop an artificial intelligence (AI)-based application to reduce time and inter-observer variability of IS analysis in rodent acute myocardial infarction (MI) models. MethodsWe used TTC/Evans blue-stained heart slice images of independent laboratories from previously published projects. Rat (n = 325 and 248 slices) and mouse (n = 77 slices) datasets were used to train deep learning segmentation models with three different neural network architectures, which were combined into a single AI analysis. AI analysis was compared with manual analysis on rat data from a training laboratory (internal data, n = 496 slices, n = 41 whole-hearts) and data from independent laboratories (external data, n = 60 and 62 slices). Additionally, two independent evaluators performed manual and AI-assisted analysis, consisting of AI-analysis and its manual correction, on internal (n = 36 slices) and external data (n = 37 slices). ResultsLins concordance correlation coefficient (CCC) between IS/AAR values from manual and AI analysis was 0.844 with 95% CI of [0.814; 0.869] for images of internal data heart slices. On external data heart slices, AI accurately annotated slice area and AAR but failed to annotate infarcted area. On internal whole-heart data, CCC between AI and AI-assisted IS/AAR was 0.894 with 95% CI of [0.812; 0.942]. AI-assisted analysis reduced evaluation time on both internal and external datasets and increased region overlap for AAR between the two independent evaluators on dependent data. ConclusionsAI-assisted analysis significantly reduced analysis time and inter-observer variability. For optimal performance, lab-specific AI training is recommended. Infarctsize-AI is available at https://infarctsize.com. Translational perspectiveMyocardial infarct size (IS) is the gold-standard end-point in shorth-term studies to assess potential cardioprotective therapies against acute myocardial infarction (AMI). However, IS quantification in rodent AMI models is time-consuming and prone to inter-observer variance. Therefore, we developed an AI-based software that can reduce analysis time and inter-observer variability and facilitate documentation, which facilitates the clinical translation of potential cardioprotective therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=34 SRC="FIGDIR/small/688527v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@187c938org.highwire.dtl.DTLVardef@1ab8bb4org.highwire.dtl.DTLVardef@160dc68org.highwire.dtl.DTLVardef@264617_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

The sodium/glucose cotransporter 2 inhibitor empagliflozin is a pharmacological chaperone of cardiac Nav1.5 channels

Diminished peak sodium current (INa) is a causative factor for slowed ventricular conduction and cardiac arrhythmias in patients with Duchenne muscular dystrophy (DMD), a devastating muscle disease triggered by dystrophin deficiency. Recently, we showed that chronic administration of the sodium/glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) restores diminished peak INa in ventricular cardiomyocytes from the dystrophin-deficient mdx mouse model of DMD. Here, we aimed to elucidate the underlying mechanism. Whole cell patch clamp studies revealed that 24 h incubation of dystrophic (mdx) ventricular cardiomyocytes with EMPA significantly increases peak INa in a concentration-dependent manner (EC50=94 nM). The enhancing effect on peak INa also occurred in dystrophic cardiac Purkinje fibers, Nav1.5-expressing tsA201 cells, as well as in dystrophic (DMDmdx) rat cardiomyocytes, and was also exerted by two other SGLT2 inhibitors. Immunofluorescence studies suggested that chronic EMPA treatment increases Nav1.5 plasma membrane expression. Peak INa enhancement by EMPA depended on functional anterograde trafficking of Nav1.5. The local anesthetic mexiletine, a well-known pharmacological chaperone of Nav1.5, enhanced peak INa in a similar manner as EMPA. Further, mutation of human Nav1.5 at a site important for local anesthetic binding (Y1767A) completely abolished the ability of both EMPA and mexiletine to enhance peak INa. Finally, the importance of Y1767 for drug-induced modulation of peak INa was confirmed by molecular docking simulations. Our findings suggest that EMPA acts as a pharmacological chaperone of Nav1.5 channels. Its chronic administration may reduce arrhythmia vulnerability in patients with DMD and other arrhythmogenic pathologies associated with diminished peak INa.

pharmacology and toxicology↗