Biology subjects

Ball, V.

Publications and source records attributed to Ball, V..

4 recordsLinked to original sources

bioRxiv2025

The effects of elevated serum lactate on measures of apparent cerebral metabolism and perfusion in the anesthetised rodent brain.

Cerebral metabolism is coupled to perfusion and can be probed using a combination of hyperpolarized carbon-13 MRI and perfusion weighted imaging. It is unknown how alterations in serum lactate affect apparent lactate exchange and pyruvate dehydrogenase flux using hyperpolarized 13C MRI, and so this pre-clinical study was designed to assess the sensitivity of MRI to detect changes in perfusion and apparent metabolism in the anesthetized rodent brain due to sodium lactate administration. Results demonstrated significant differences in cerebral blood flow between the saline and sodium L-lactate administered at 0.5 g/kg (112 {+/-} 5 vs 127 {+/-} 2 mL/100g/min), saline and sodium L-lactate administered at 1 g/kg (112 {+/-} 5 vs 90 {+/-} 5 mL/100g/min), and between sodium L-lactate at 0.5 g/kg and sodium L-lactate at 1 g/kg (127 {+/-} 2 vs 90 {+/-} 5 mL/100g/min). There was excellent reproducibility of cerebral perfusion measurements (ICC > 0.95) between observers, indicating high reliability in these results. There were significant differences in [1-13C] lactate:[1-13C] pyruvate between saline vs 0.5 g/kg (0.22 {+/-} 0.05 vs 0.59 {+/-} 0.15) and saline vs 1 g/kg (0.22 {+/-} 0.05 vs 0.62 {+/-} 0.04), but no significant differences in 13C bicarbonate:[1-13C] pyruvate (p = 0.1). In conclusion, perfusion and [1-13C] lactate:[1-13C] pyruvate are sensitive to changes in serum lactate, but 13C bicarbonate:[1-13C] pyruvate were not. This has implications for brain studies using [1-13C] pyruvate, and understanding the impact of serum lactate on clinical hyperpolarised imaging is needed.

neuroscience↗

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↗

bioRxiv2022

AICAR prevents doxorubicin-induced heart failure in rats by ameliorating cardiac atrophy and improving fatty acid oxidation

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to functional cardiac decline and ultimately, congestive heart failure (HF). Impaired mitochondrial function and energetics are thought to be key factors driving progression into HF. We have previously shown in a rat model of chronic intravenous DOX-administration that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and oxidative metabolism, including fatty acid oxidation. We hypothesized that AMPK activation could restore mitochondrial number and function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. We therefore set out to assess whether 5-aminoimidazole-4-carboxamide 1-{beta}-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this clinically relevant rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. We show that this could be due to normalisation of substrate supply to the heart, as AICAR prevented DOX-induced dyslipidaemia. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, despite no increase in mitochondrial number. In addition, we found that AICAR prevented excessive myocardial atrophy, and RNAseq analysis showed that this may be due to normalisation of protein synthesis pathways, which are impaired in DOX-treated rat hearts. Taken together, these results show promise for use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac mass and improve cardiac function.

biochemistry↗

bioRxiv2018

Assessing the effect of hypoxia on cardiac metabolism using hyperpolarized 13C magnetic resonance spectroscopy

Abstract summaryHypoxia plays a role in many diseases and can have a wide range of effects on cardiac metabolism depending on the extent of the hypoxic insult. Non-invasive imaging methods could shed valuable light on the metabolic effects of hypoxia on the heart in vivo. Hyperpolarized carbon-13 magnetic resonance spectroscopy (HP 13C MRS) in particular is an exciting technique for imaging metabolism that could provide such information.\n\nThe aim of our work was, therefore, to establish whether hyperpolarized 13C MRS can be used to assess the in vivo response of cardiac metabolism to systemic acute and chronic hypoxic exposure. Groups of healthy male Wistar rats were exposed to either acute (30 minutes), one week or three weeks of hypoxia. In vivo MRS of hyperpolarized [1-13C]pyruvate was carried out along with assessments of physiological parameters and ejection fraction. No significant changes in heart rate, respiration rate, or ejection fraction were observed at any timepoint. Haematocrit was elevated after one week and three weeks of hypoxia.\n\nThirty minutes of hypoxia resulted in a significant reduction in pyruvate dehydrogenase (PDH) flux, whereas one or three weeks of hypoxia resulted in a PDH flux that was not different to normoxic animals. Conversion of hyperpolarized [1-13C]pyruvate into [1-13C]lactate was elevated following acute hypoxia, suggestive of enhanced anaerobic glycolysis. Elevated HP pyruvate to lactate conversion was also seen at the one-week timepoint, in concert with an increase in lactate dehydrogenase (LDH) expression. Following three weeks of hypoxic exposure, cardiac metabolism was comparable to that observed in normoxia.\n\nWe have successfully visualized of the effects of systemic hypoxia on cardiac metabolism using hyperpolarized 13C MRS, with differences observed following 30 minutes and 1 week of hypoxia. This demonstrates the potential of in vivo hyperpolarized 13C MRS data for assessing the cardiometabolic effects of hypoxia in disease.

physiology↗