Biology subjects

Aksentijevic, D.

Publications and source records attributed to Aksentijevic, D..

4 recordsLinked to original sources

bioRxiv2025

Bat power-metabolic profiling of the Egyptian fruit bat Rousettus aegyptiacus reveals distinctive cardiac adaptations

AimThe present study aimed to elucidate which pathways contribute to cardiometabolic adaptation in Egyptian fruit bats. MethodsUtilising cardiac tissues from Egyptian fruit bats (Rousettus aegyptiacus) and C57BL/6J mice, we combined liquid chromatography-mass spectrometry metabolic profiling, non-targeted 1H NMR spectroscopy, and in silicocomputational modelling using the genome-scale mammalian network CardioNet. Main FindingsOur analyses revealed that bat hearts exhibit a distinct metabolic profile characterised by depleted glycogen reserves and increased reliance on lipid oxidation to meet energy demands. Notably, bat hearts displayed elevated fluxes in oxidative phosphorylation, {beta}-oxidation of long-chain fatty acids, and the Krebs cycle, alongside reduced amino acid catabolism. These findings suggest that bats have evolved unique metabolic strategies to support the high-energy demands of flight, maintaining cardiac function without succumbing to pathological remodelling. ConclusionsThis study provides the first comprehensive insight into the metabolic adaptations in the cardiac tissue of a bat species, contributing to our understanding of how these mammals endure extreme physiological stresses. Integrating metabolomics with computational modelling offers a powerful approach to studying metabolic adaptations in non-model species, potentially informing therapeutic strategies for human cardiac conditions.

systems biology↗

bioRxiv2025

Immunomodulation by AZD1656 reverses cardiac dysfunction, metabolic remodelling and reduces infarct size in type 2 diabetic cardiomyopathy

Type 2 diabetes (T2D) precipitates diabetic cardiomyopathy (dbCM), a condition characterized by chronic inflammation, metabolic dysregulation and impaired cardiac performance. Here we show that the glucokinase activator AZD1656, originally developed for glycaemic control but later identified to have immunomodulatory effects, reverses cardiac dysfunction and metabolic remodelling in dbCM. In obese, hyperglycaemic db/db mice with diastolic dysfunction, six weeks of AZD1656 treatment improved myocardial performance, reduced infarct size and enhanced post-ischaemic recovery. Integrated metabolic, functional and histological analyses revealed restoration of mitochondrial metabolism and attenuation of fibrosis. Mechanistically, AZD1656 remodelled the cardiac immune landscape by promoting regulatory T-cell infiltration. These findings demonstrate a link between cardiac inflammation and metabolic remodelling in dbCM and highlight that modulation of immune cells and metabolism can protect the diabetic heart. Targeting immunometabolic pathways may therefore offer a therapeutic strategy to alleviate cardiac dysfunction and reduce infarct vulnerability in T2D

physiology↗

bioRxiv2024

Altered systemic bioenergetic reserve in chronic kidney disease predisposes hearts to worse functional outcomes

BackgroundCardiovascular mortality in chronic kidney disease (CKD) remains disproportionately high, yet the mechanisms linking renal dysfunction to cardiac vulnerability are incompletely understood. Uraemic cardiomyopathy is increasingly recognised as a systemic metabolic disease, but the contribution of multi-organ bioenergetic failure in cardiac dysfunction is poorly defined. HypothesisCKD induces metabolic remodelling across peripheral organs (liver, skeletal muscle, and kidneys) depleting systemic bioenergetic reserve, compromising cardiometabolic flexibility and stress resilience. MethodsUsing CKD models of different aetiologies in rats (glomerulosclerosis by partial nephrectomy and interstitial fibrosis by adenine diet) we investigated cardiac and systemic metabolic remodelling. ResultsIrrespective of aetiology, renal insufficiency resulted in cardiac dysfunction including impaired functional recovery after 25-minutes ischaemia. 1H NMR metabolomic analysis revealed perturbations of systemic metabolism in CKD were more severe than cardiometabolic changes with alterations of skeletal muscle, liver, and kidney metabolism indicating reduced systemic bioenergetic reserve. This pre-clinical observation was recapitulated in human CKD patients where phosphorus magnetic resonance spectroscopy assessment of exercising lower leg muscle identified bioenergetic deficiencies preventing maximal force generation. Thus, both heart and skeletal muscles in CKD have impaired response to metabolic stress. ConclusionsCKD induces multi-organ metabolic failure that limits the hearts ability to meet energetic demands under stress. This study identifies systemic bioenergetic collapse as a contributing factor to uraemic cardiomyopathy, thus targeting peripheral organ metabolism may represent a novel therapeutic strategy to improve cardiac outcomes in CKD. Key learning pointsO_ST_ABSWhat Was KnownC_ST_ABSCKD significantly increases cardiovascular risk, but the cause of heart failure in these patients is largely attributed to cardiac pathology alone whilst the potential contribution of systemic metabolic dysfunction remains unexplored. What This Study AddsUtilising clinical and pre-clinical approach we show that CKD triggers widespread metabolic dysfunction in the liver, skeletal muscle, and kidney, depleting the systemic bioenergetic reserve and impairing the hearts ability to handle metabolic stress. Potential ImpactThese findings show uraemic cardiomyopathy is a multi-organ metabolic disease and targeting peripheral metabolic dysfunction could offer a new therapeutic strategy to enhance cardiac resilience by restoring systemic energy balance.

physiology↗

bioRxiv2023

Naked mole rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles

The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, RNAseq and metabolomics of cardiac tissue from naked mole-rats was compared to other African mole-rat genera. We identified metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1 was observed while downstream hypoxia responsive-genes were down regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts showed reduced succinate build-up during ischemia and negligible tissue damage following ischemia-reperfusion injury. These adaptive evolutionary traits reflect a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span. One Sentence SummaryNaked mole-rats have metabolic adaptations distinct from other subterranean genera rendering them resistant to cardiovascular pathology.

physiology↗