Biology subjects

Delbridge, L. M. D.

Publications and source records attributed to Delbridge, L. M. D..

7 recordsLinked to original sources

bioRxiv2026

Sex differences in cardiomyocyte proteomic responses to the cardiotoxic chemotherapy drug doxorubicin

Anthracyclines, including doxorubicin, are widely used chemotherapeutic agents, but dose-dependent cardiotoxicity limits their clinical utility and increases the risk of heart failure in cancer survivors. In paediatric patients, female sex is a significant risk factor for anthracycline-associated cardiotoxicity, yet pre-clinical studies rarely investigate sex differences in immature hearts. Here, we provide a proteomic dataset from primary cardiomyocytes, isolated from postnatal day 2 rat hearts and treated with a clinically relevant concentration of doxorubicin. Analysis of proteins present in all samples identified candidates previously shown to be regulated by doxorubicin in adult hearts, as well as candidates that may be specifically regulated in young hearts. This dataset provides a resource for generating hypotheses on molecular mechanisms contributing to sex differences in juvenile doxorubicin-induced cardiotoxicity.

molecular biology↗

bioRxiv2025

Multicenter HFpEF study identifies sex disparity linked with two discrete cardiac proteomic signatures

Heart failure with preserved ejection fraction (HFpEF) is epidemic, with an incidence exceeding that of heart failure with reduced ejection fraction (HFrEF). Sex differences in HFpEF phenotype have been observed, particularly linked to aging and metabolic comorbidities in women. Here, we report a multi-centre proteomic analysis of HFpEF and HFrEF cardiac samples. Using tissues and clinical data derived from multiple institutional biobanks, in-depth characterization of the proteome of ventricular samples was undertaken. Relative to HFrEF, the HFpEF cohort exhibited minimal proteome composition overlap and pronounced heterogeneity. A key finding of this investigation is that sex per se did not confer a distinctive proteomic HFpEF signature. Rather, two HFpEF proteomic profiles were identified, differing significantly in sex ratios. The identification of two Clusters revealed that HFpEF has two predominant proteomic signatures at the molecular level, marked by differences in the extent and nature of structural and contractile machinery and by local cellular and ECM communications. Upstream regulator analysis identified various molecular leads to be pursued in defining these two HFpEF profiles. Our findings offer specific opportunities for new exploration of therapeutic options to target the spectrum of HFpEF proteomic diversity and identify potential drug targeting prospects.

molecular biology↗

bioRxiv2024

Methods for detection of cardiac glycogen-autophagy

Glycogen-autophagy ( glycophagy) is a selective autophagy process involved in delivering glycogen to the lysosome for bulk degradation. Glycophagy protein intermediaries include STBD1 as a glycogen tagging receptor, delivering the glycogen cargo into the forming phagosome by partnering with the Atg8 homolog, GABARAPL1. Glycophagy is emerging as a key process of energy metabolism and development of reliable tools for assessment of glycophagy activity is an important priority. Here we show that antibodies raised against the N-terminus of the GABARAPL1 protein (but not the full-length protein) detected a specific endogenous GABARAPL1 immunoblot band at 18kDa. A stable GFP-GABARAPL1 cardiac cell line was used to quantify GABARAPL1 lysosomal flux via measurement of GFP puncta in response to lysosomal inhibition with bafilomycin. Endogenous glycophagy flux was quantified in primary rat ventricular myocytes by the extent of glycogen accumulation with bafilomycin combined with chloroquine treatment (no effect observed with bafilomycin or chloroquine alone). In wild-type isolated mouse hearts, bafilomycin alone and bafilomycin combined with chloroquine (but not chloroquine alone) elicited a significant increase in glycogen content signifying basal glycophagy flux. Collectively, these methodologies provide a comprehensive toolbox for tracking cardiac glycophagy activity to advance research into the role of glycophagy in health and disease.

molecular biology↗

bioRxiv2024

Mechanical loading reveals an intrinsic cardiomyocyte stiffness contribution to diastolic dysfunction in murine cardiometabolic disease

Cardiometabolic syndromes including diabetes and obesity are associated with occurrence of heart failure with diastolic dysfunction. There are no specific treatments for diastolic dysfunction, and therapies to manage symptoms have limited efficacy. Understanding of the cardiomyocyte origins of diastolic dysfunction is an important priority to identify new therapeutics. The investigative goal was to experimentally define in vitro stiffness properties of isolated cardiomyocytes derived from rodent hearts exhibiting diastolic dysfunction in vivo in response to dietary induction of cardiometabolic disease. Male mice fed a high fat/sugar diet (HFSD vs control) exhibited diastolic dysfunction (echo E/e doppler ratio). Intact paced cardiomyocytes were functionally investigated in three conditions: non-loaded, loaded and stretched. Mean stiffness of HFSD cardiomyocytes was 70% higher than control. E/e for the origin hearts was elevated by 35%. A significant relationship was identified between in vitro cardiomyocyte stiffness and in vivo dysfunction severity. With conversion from non-loaded to loaded condition, the decrement in maximal sarcomere lengthening rate was more accentuated in HFSD cardiomyocytes (vs control). With stretch, the Ca2+ transient decay time course was prolonged. With increased pacing, cardiomyocyte stiffness was elevated, yet diastolic Ca2+ elevation was attenuated. Our findings show unequivocally that cardiomyocyte mechanical dysfunction cannot be detected by analysis of non-loaded shortening. Collectively, these findings demonstrate that a component of cardiac diastolic dysfunction in cardiometabolic disease is derived from cardiomyocyte stiffness. Differential responses to load, stretch and pacing suggest that a previously undescribed alteration in myofilament-Ca2+ interaction contributes to intrinsic cardiomyocyte stiffness in cardiometabolic disease. KEY POINTSO_LIUnderstanding cardiomyocyte stiffness components is an important priority for identifying new therapeutics for diastolic dysfunction, a key feature of cardiometabolic disease. C_LIO_LIIn this study cardiac function was measured in vivo (echocardiography) for mice fed a high-fat/sugar diet (HFSD, [≥]25weeks). Performance of intact isolated cardiomyocytes derived from the same hearts was measured during pacing under non-loaded, loaded and stretched conditions in vitro. C_LIO_LICalibrated cardiomyocyte stretches demonstrated that stiffness (stress/strain) was elevated in HFSD cardiomyocytes in vitro and correlated with diastolic dysfunction (E/e) in vivo. HFSD cardiomyocyte Ca2+ transient decay was prolonged in response to stretch. Stiffness was accentuated with pacing increase while the elevation in diastolic Ca2+ was attenuated. C_LIO_LIData show unequivocally that cardiomyocyte mechanical dysfunction cannot be detected by analysis of non-loaded shortening. C_LIO_LIThese findings suggest that stretch-dependent augmentation of the myofilament-Ca2+ response during diastole partially underlies elevated cardiomyocyte stiffness and diastolic dysfunction of hearts of animals with cardiometabolic disease. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/581448v3_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1a2fd4corg.highwire.dtl.DTLVardef@1a398ceorg.highwire.dtl.DTLVardef@184ff46org.highwire.dtl.DTLVardef@936923_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOAbstract Figure LegendC_FLOATNO Understanding cardiomyocyte stiffness components is an important priority for identifying new therapeutics for diastolic dysfunction, a key feature of cardiometabolic disease. In this study cardiac function was measured in vivo (echocardiography) for mice fed a high-fat/sugar diet (HFSD, [≥]25weeks). Performance of intact isolated cardiomyocytes derived from the same hearts was measured during pacing under non-loaded, loaded and stretched conditions in vitro. Calibrated cardiomyocyte stretches demonstrated that stiffness was elevated in HFSD cardiomyocytes in vitro and correlated with diastolic dysfunction (E/e) in vivo. These findings show that stiff hearts are characterized by stiff cardiomyocytes in metabolic disease. C_FIG

physiology↗

bioRxiv2022

Myocardial deformation imaging by 2D speckle tracking echocardiography for assessment of diastolic dysfunction in murine cardiopathology

Diastolic dysfunction is increasingly identified as a key, early onset subclinical condition characterizing cardiopathologies of rising prevalence, including diabetic heart disease and heart failure with preserved ejection fraction (HFpEF). Diastolic dysfunction characterization has important prognostic value in management of disease outcomes. Validated tools for in vivo monitoring of diastolic function in rodent models of diabetes are required for progress in pre-clinical cardiology studies. 2D speckle tracking echocardiography has emerged as a powerful tool for evaluating cardiac wall deformation throughout the cardiac cycle. The aim of this study was to examine the applicability of 2D speckle tracking echocardiography for comprehensive global and regional assessment of diastolic function in a pre-clinical murine model of cardio-metabolic disease. Type 2 diabetes (T2D) was induced in C57Bl/6 male mice using a high fat high sugar dietary intervention for 20 weeks. Significant impairment in left ventricle peak diastolic strain rate was evident in longitudinal, radial and circumferential planes in T2D mice. Peak diastolic velocity was similarly impaired in the longitudinal and radial planes. Regional analysis of longitudinal peak diastolic strain rate revealed that the anterior free left ventricular wall is particularly susceptible to T2D-induced diastolic dysfunction. These findings provide a significant advance on characterization of diastolic dysfunction in a pre-clinical mouse model of cardiopathology and offer a comprehensive suite of benchmark values for future pre-clinical cardiology studies.

physiology↗

bioRxiv2021

Protective role of the Atg8 1 homologue Gabarapl1 in regulating cardiomyocyte glycophagy in diabetic heart disease

Diabetic heart disease is highly prevalent and characterized by diastolic dysfunction. The mechanisms of diabetic heart disease are poorly understood and no targeted therapies are available. Here we show that the diabetic myocardium (type 1 and type 2) is characterized by marked glycogen elevation and ectopic cellular localization - a paradoxical metabolic pathology given suppressed cardiomyocyte glucose uptake in diabetes. We demonstrate involvement of a glycogen-selective autophagy pathway ( glycophagy) defect in mediating this pathology. Genetically manipulated deficiency of Gabarapl1, an Atg8 autophagy homologue, induces cardiac glycogen accumulation and diastolic dysfunction. Stbd1, the Gabarapl1 cognate autophagosome partner is identified as a unique component of the early glycoproteome response to hyperglycemia in cardiac, but not skeletal muscle. Cardiac-targeted in vivo Gabarapl1 gene delivery normalizes glycogen levels, diastolic function and cardiomyocyte mechanics. These findings reveal that cardiac glycophagy is a key metabolic homeostatic process perturbed in diabetes that can be remediated by Gabarapl1 intervention.

molecular biology↗

bioRxiv2018

Insights on the impact of mitochondrial organisation on bioenergetics in high-resolution computational models of cardiac cell architecture

Recent electron microscopy data have revealed that cardiac mitochondria are not arranged in crystalline columns, but are organised with several mitochondria aggregated into columns of varying sizes often spanning the cell cross-section. This raises the question - how does the mitochondrial arrangement affect the metabolite distributions within cardiomyocytes and their impact on force dynamics? Here we employed finite element modelling of cardiac bioenergetics, using computational meshes derived from electron microscope images, to address this question. Our results indicate that heterogeneous mitochondrial distributions can lead to significant spatial variation across the cell in concentrations of inorganic phosphate, creatine (Cr) and creatine phosphate (PCr). However, our model predicts that sufficient activity of the creatine kinase (CK) system, coupled with rapid diffusion of Cr and PCr, maintains near uniform ATP and ADP ratios across the cell cross sections. This homogenous distribution of ATP and ADP should also evenly distribute force production and twitch duration with contraction. These results suggest that the PCr shuttle, and associated enzymatic reactions, act to maintain uniform force dynamics in the cell despite the heterogeneous mitochondrial organization. However, our model also predicts that under hypoxia - activity of mitochondrial CK enzyme and diffusion of high-energy phosphate compounds may be insufficient to sustain uniform ATP/ADP distribution and hence force generation.

systems biology↗