Biology subjects

Laustsen, C.

Publications and source records attributed to Laustsen, C..

3 recordsLinked to original sources

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↗

bioRxiv2022

Metabolic clearance rate modeling: A translational approach to quantifying cerebral metabolism using hyperpolarized pyruvate.

Hyperpolarized carbon-13 MRI is a promising technique for in vivo metabolic interrogation of alterations between health and disease. This study introduces a model-free formalism for quantifying the metabolic information in hyperpolarized imaging. This study investigated a novel model-free perfusion and metabolic clearance rate (MCR) model in pre-clinical stroke and in the healthy human brain. Simulations showed that the proposed model was robust to perturbations in T1, transmit B1, and kPL. A significant difference in ipsilateral vs contralateral pyruvate derived cerebral blood flow (CBF) was detected in rats (140 {+/-} 2 vs 89 {+/-} 6 mL/100g/min, p < 0.01, respectively) and pigs (139 {+/-} 12 vs 95 {+/-} 5 mL/100g/min, p = 0.04, respectively), along with an increase in fractional metabolism (26 {+/-} 5 vs 4 {+/-} 2 %, p < 0.01, respectively) in the rodent brain. In addition, a significant increase in ipsilateral vs contralateral MCR (0.034 {+/-} 0.007 vs 0.017 {+/-} 0.02 s-1, p = 0.03, respectively) and a decrease in mean transit time (MTT) (31 {+/-} 8 vs 60 {+/-} 2, p = 0.04, respectively) was observed in the porcine brain. In conclusion, MCR mapping is a simple and robust approach to the post-processing of hyperpolarized magnetic resonance imaging.

physiology↗

bioRxiv2021

In vivo evidence that SORL1, encoding the endosomal recycling receptor SORLA, can function as a causal gene in Alzheimer's Disease

The few established causal genes in Alzheimers disease (AD), mutations in APP and PSENs, have been functionally characterized using biomarkers, capturing an in vivo profile reflecting the diseases initial preclinical phase. SORL1, a gene encoding the endosome recycling receptor SORLA, epidemiologically behaves as a causal gene when truncating mutations lead to partial loss of protein function. Here, in an effort to test whether SORL1 can indeed function as an AD causal gene, we used CRISPR-Cas9-based gene editing to develop a novel model of SORL1 haploinsufficiency in Gottingen Minipigs taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young minipigs was found to phenocopy the preclinical in vivo profile of AD observed with other causal genes, resulting in spinal fluid abnormalities in A{beta} and tau, with no evident neurodegeneration or amyloid plaque formation. These studies provide functional support that SORL1 is a bona fide causal gene in AD, and when taken together with recent insight on other AD-causal genes, support the idea that dysfunctional endosomal recycling is a dominant pathogenic pathway in the disease.

neuroscience↗