RESUMEN
Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson's disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [31P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.-Murray, A. J., Knight, N. S., Cole, M. A., Cochlin, L. E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M. K., Atherton, H. J., Schroeder, M. A., Deacon, R. M. J., Kashiwaya, Y., King, M. T., Pawlosky, R., Rawlins, J. N. P., Tyler, D. J., Griffin, J. L., Robertson, J., Veech, R. L., Clarke, K. Novel ketone diet enhances physical and cognitive performance.
Asunto(s)
Cognición/fisiología , Dieta , Ingestión de Energía/fisiología , Metabolismo Energético/fisiología , Conducta Alimentaria/fisiología , Cetonas/administración & dosificación , Animales , Colesterol/sangre , Carbohidratos de la Dieta/metabolismo , Grasas de la Dieta/metabolismo , Insulina/metabolismo , Masculino , Ratas Wistar , Triglicéridos/sangreRESUMEN
BACKGROUND: Whether the myocardium in nonischemic heart failure experiences oxygen limitation remains a long-standing controversy. We addressed this question in patients with dilated cardiomyopathy (DCM) using a dual approach. First, we tested the changes in myocardial oxygenation between rest and stress states, using oxygenation-sensitive cardiovascular magnetic resonance. Second, we sought to assess the functional consequences of oxygen limitation at rest by measuring myocardial energetics before and after short-term oxygen supplementation. METHODS AND RESULTS: Twenty-six subjects (14 DCM and 12 normal) underwent cardiac magnetic resonance imaging at 3 Tesla to assess cardiac volumes, function, oxygenation, and first-pass perfusion (0.03 mmol/kg Gd-DTPA bolus) at stress and rest (4-6 minutes IV adenosine, 140 µg/kg per minute). Signal intensity change (SIΔ) and myocardial perfusion reserve index (MPRI) were measured from oxygenation and perfusion images, respectively. Furthermore, the effect of oxygen supplementation on resting myocardial energy metabolism was tested using (31)P MR spectroscopy, measuring PCr/ATP ratios in both groups at baseline and after 4 hours of oxygen via facemask in the DCM group. During stress, there were equivalent rises in rate pressure product in both groups (DCM, 76±15% and normal, 79±9%; P=0.84). MPRI was significantly reduced in DCM (1.51±0.11 versus normal 1.86±0.10; P=0.03). However, there was no difference in oxygenation between groups: SIΔ in DCM 17±3% versus normal 20±2% (P=0.38). Furthermore, at a left ventricular segmental level, there was no correlation between oxygenation-sensitive SIΔ and MPRI (R=0.06; P=0.43). Resting PCr/ATP was reduced in DCM (1.66±0.07 versus normal 2.12±0.06; P=0.002). With oxygen supplementation, there was no change in PCr/ATP (1.61±0.08; P=0.58; Δ=0.04±0.05). There was also no effect of oxygen on systolic function (ejection fraction pre oxygen, 34±1%; post oxygen, 36±2%; P=0.46; Δ 2±1%). CONCLUSIONS: Our results demonstrate dissociation between microvascular dysfunction and oxygenation in DCM, suggesting that the impairment of perfusion is not sufficient to cause deoxygenation during stress. Cardiac energetics are unaffected by oxygen supplementation, indicating the absence of relevant myocardial hypoxia at rest. Our study suggests that novel treatments for nonischemic heart failure should focus on efforts to directly target cardiomyocyte function and metabolism rather than oxygen delivery and microvascular function.
Asunto(s)
Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/fisiopatología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Cardiomiopatía Dilatada/terapia , Estudios de Casos y Controles , Circulación Coronaria/fisiología , Prueba de Esfuerzo , Femenino , Insuficiencia Cardíaca/terapia , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Consumo de Oxígeno/fisiología , Terapia por Inhalación de OxígenoRESUMEN
AIMS: Hypertrophic cardiomyopathy (HCM) is the commonest cause of sudden cardiac death in the young, with an excess of exercise-related deaths. The HCM sarcomere mutations increase the energy cost of contraction and impaired resting cardiac energetics has been documented by measurement of phosphocreatine/ATP (PCr/ATP) using (31)Phosphorus MR Spectroscopy ((31)P MRS). We hypothesized that cardiac energetics are further impaired acutely during exercise in HCM and that this would have important functional consequences. METHODS AND RESULTS: (31)P MRS was performed in 35 HCM patients and 20 age- and gender-matched normal volunteers at rest and during leg exercise with 2.5 kg ankle weights. Peak left-ventricular filling rates (PFRs) and myocardial perfusion reserve (MPRI) were calculated during adenosine stress. Resting PCr/ATP was significantly reduced in HCM (HCM: 1.71 ± 0.35, normal 2.14 ± 0.35 P < 0.0001). During exercise, there was a further reduction in PCr/ATP in HCM (1.56 ± 0.29, P = 0.02 compared with rest) but not in normals (2.16 ± 0.26, P = 0.98 compared with rest). There was no correlation between PCr/ATP reduction and cardiac mass, wall thickness, MPRI, or late-gadolinium enhancement. PFR and PCr/ATP were significantly correlated at rest (r = 0.48, P = 0.02) and stress (r = 0.53, P = 0.01). CONCLUSION: During exercise, the pre-existing energetic deficit in HCM is further exacerbated independent of hypertrophy, perfusion reserve, or degree of fibrosis. This is in keeping with the change at the myofilament level. We offer a potential explanation for exercise-related diastolic dysfunction in HCM.
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Cardiomiopatía Hipertrófica/metabolismo , Ejercicio Físico/fisiología , Disfunción Ventricular Izquierda/etiología , Adenosina Trifosfato/metabolismo , Adulto , Presión Sanguínea/fisiología , Estudios de Casos y Controles , Diástole , Metabolismo Energético , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Angiografía por Resonancia Magnética , Imagen por Resonancia Cinemagnética , Espectroscopía de Resonancia Magnética , Masculino , Fosfocreatina/metabolismo , Estudios Prospectivos , Volumen Sistólico/fisiología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
Exposure to high altitude is associated with sustained, but reversible, changes in cardiac mass, diastolic function, and high-energy phosphate metabolism. Whilst the underlying mechanisms remain elusive, tissue hypoxia increases generation of reactive oxygen species (ROS), which can stabilize hypoxia-inducible factor (HIF) transcription factors, bringing about transcriptional changes that suppress oxidative phosphorylation and activate autophagy. We therefore investigated whether oral supplementation with an antioxidant, Coenzyme Q10, prevented the cardiac perturbations associated with altitude exposure. Twenty-three volunteers (10 male, 13 female, 46±3 years) were recruited from the 2009 Caudwell Xtreme Everest Research Treks and studied before, and within 48 h of return from, a 17-day trek to Everest Base Camp, with subjects receiving either no intervention (controls) or 300 mg Coenzyme Q10 per day throughout altitude exposure. Cardiac magnetic resonance imaging and echocardiography were used to assess cardiac morphology and function. Following altitude exposure, body mass fell by 3 kg in all subjects (p<0.001), associated with a loss of body fat and a fall in BMI. Post-trek, left ventricular mass had decreased by 11% in controls (p<0.05) and by 16% in Coenzyme Q10-treated subjects (p<0.001), whereas mitral inflow E/A had decreased by 18% in controls (p<0.05) and by 21% in Coenzyme Q10-treated subjects (p<0.05). Coenzyme Q10 supplementation did not, therefore, prevent the loss of left ventricular mass or change in diastolic function that occurred following a trek to Everest Base Camp.
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Volumen Cardíaco/efectos de los fármacos , Montañismo/fisiología , Ubiquinona/análogos & derivados , Vitaminas/farmacología , Tejido Adiposo/anatomía & histología , Administración Oral , Adulto , Antioxidantes/farmacología , Presión Sanguínea/fisiología , Índice de Masa Corporal , Hipoxia de la Célula/fisiología , Diástole/efectos de los fármacos , Suplementos Dietéticos , Ecocardiografía , Femenino , Ventrículos Cardíacos/efectos de los fármacos , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fosfatos/metabolismo , Ubiquinona/farmacologíaRESUMEN
Neuronal glucose uptake was thought to be independent of insulin, being facilitated by glucose transporters GLUT1 and GLUT3, which do not require insulin signaling. However, it is now known that components of the insulin-mediated glucose uptake pathway, including neuronal insulin synthesis and the insulin-dependent glucose transporter GLUT4, are present in brain tissue, particularly in the hippocampus. There is considerable recent evidence that insulin signaling is crucial to optimal hippocampal function. The physiological basis, however, is not clear. We propose that while noninsulin-dependent GLUT1 and GLUT3 transport is adequate for resting needs, the surge in energy use during sustained cognitive activity requires the additional induction of insulin-signaled GLUT4 transport. We studied hippocampal high-energy phosphate metabolism in eight healthy volunteers, using a lipid infusion protocol to inhibit insulin signaling. Contrary to conventional wisdom, it is now known that free fatty acids do cross the blood-brain barrier in significant amounts. Energy metabolism within the hippocampus was assessed during standardized cognitive activity. (31)Phosphorus magnetic resonance spectroscopy was used to determine the phosphocreatine (PCr)-to-adenosine triphosphate (ATP) ratio. This ratio reflects cellular energy production in relation to concurrent cellular energy expenditure. With lipid infusion, the ratio was significantly reduced during cognitive activity (PCr/ATP 1.0 ± 0.4 compared with 1.4 ± 0.4 before infusion, P = 0.01). Without lipid infusion, there was no reduction in the ratio during cognitive activity (PCr/ATP 1.5 ± 0.3 compared with 1.4 ± 0.4, P = 0.57). This provides supporting evidence for a physiological role for insulin signaling in facilitating increased neuronal glucose uptake during sustained cognitive activity. Loss of this response, as may occur in type 2 diabetes, would lead to insufficient neuronal energy availability during cognitive activity.
RESUMEN
OBJECTIVE: To determine the effects of short-term exercise training on cardiac function and metabolism during rest and physical exercise in patients with heart failure from dilated cardiomyopathy (DCM). DESIGN: Patients with DCM (n=15, age 58±2 years, NYHA class I-III) were studied before and after 8 weeks of cycle exercise for 20 min, five times per week. MAIN OUTCOME MEASURES: Cardiac volumes, function and high energy phosphate metabolism were measured using cardiac magnetic resonance during rest and 7 min of acute physical exercise (leg-raising). RESULTS: At baseline, average left ventricular ejection fraction (LVEF) was 38±3%, which did not alter during 7 min of exercise. After 8 weeks of home exercise training, there was a 16% improvement in resting LVEF to 44±3% (p<0.01). Training caused a further 20% improvement in LVEF (p<0.05) during acute physical exercise. There was a negative correlation between subjects' baseline level of exercise and change in LVEF (r=-0.67, p<0.05), with sedentary patients having the greatest improvement. Cardiac phosphocreatine (PCr) to ATP ratio did not change during acute physical exercise or after exercise training. CONCLUSIONS: Short-term exercise training improves resting LVEF and LVEF with acute physical exercise with sedentary patients having the greatest improvement. There were no changes in cardiac PCr to ATP, before or after exercise training, suggesting that the improved cardiac function was not caused by improved energetics. Therefore, peripheral factors likely underlie the improved cardiac function in patients with heart failure after short-term exercise.
Asunto(s)
Cardiomiopatía Dilatada/terapia , Metabolismo Energético , Terapia por Ejercicio/métodos , Ejercicio Físico/fisiología , Fosfatos/metabolismo , Descanso/fisiología , Función Ventricular , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Cinemagnética , Masculino , Persona de Mediana Edad , Volumen Sistólico , Factores de Tiempo , Resultado del TratamientoRESUMEN
(R)-3-Hydroxybutyl (R)-3-hydroxybutyrate (ketone monoester) has been developed as an oral source of ketones, which may be utilized for energy. In a 28-day toxicity study, Crl:WI (Wistar) rats received diets containing, as 30% of the calories, ketone monoester (12 and 15 g/kg body weight/day for male and female rats, respectively). Control groups received either carbohydrate- or fat-based diets. Rats in the test group consumed less feed and gained less weight than control animals; similar findings have been documented in studies of ketogenic diets. Between-group differences were noted in selected hematology, coagulation, and serum chemistry parameters; however, values were within normal physiological ranges and/or were not accompanied by other changes indicative of toxicity. Upon gross and microscopic evaluation, there were no findings associated with the ketone monoester. In a developmental toxicity study, pregnant Crl:WI (Han) rats were administered 2g/kg body weight/day ketone monoester or water (control) via gavage on days 6 through 20 of gestation. No Caesarean-sectioning or litter parameters were affected by the test article. The overall incidence of fetal alterations was higher in the test group; however, there were no specific alterations attributable to the test substance. The results of these studies support the safety of ketone monoester.
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Dieta , Hidroxibutiratos/toxicidad , Cetonas/toxicidad , Reproducción/efectos de los fármacos , Pruebas de Toxicidad Subaguda , Animales , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Ingestión de Energía , Metabolismo Energético/efectos de los fármacos , Ésteres , Femenino , Hidroxibutiratos/metabolismo , Cetonas/metabolismo , Masculino , Exposición Materna/efectos adversos , Ratas , Ratas WistarRESUMEN
BACKGROUND: Carnitine acetyltransferase catalyzes the reversible conversion of acetyl-coenzyme A (CoA) into acetylcarnitine. The aim of this study was to use the metabolic tracer hyperpolarized [2-(13)C]pyruvate with magnetic resonance spectroscopy to determine whether carnitine acetyltransferase facilitates carbohydrate oxidation in the heart. METHODS AND RESULTS: Ex vivo, following hyperpolarized [2-(13)C]pyruvate infusion, the [1-(13)C]acetylcarnitine resonance was saturated with a radiofrequency pulse, and the effect of this saturation on [1-(13)C]citrate and [5-(13)C]glutamate was observed. In vivo, [2-(13)C]pyruvate was infused into 3 groups of fed male Wistar rats: (1) controls, (2) rats in which dichloroacetate enhanced pyruvate dehydrogenase flux, and (3) rats in which dobutamine elevated cardiac workload. In the perfused heart, [1-(13)C]acetylcarnitine saturation reduced the [1-(13)C]citrate and [5-(13)C]glutamate resonances by 63% and 51%, respectively, indicating a rapid exchange between pyruvate-derived acetyl-CoA and the acetylcarnitine pool. In vivo, dichloroacetate increased the rate of [1-(13)C]acetylcarnitine production by 35% and increased the overall acetylcarnitine pool size by 33%. Dobutamine decreased the rate of [1-(13)C]acetylcarnitine production by 37% and decreased the acetylcarnitine pool size by 40%. CONCLUSIONS: Hyperpolarized (13)C magnetic resonance spectroscopy has revealed that acetylcarnitine provides a route of disposal for excess acetyl-CoA and a means to replenish acetyl-CoA when cardiac workload is increased. Cycling of acetyl-CoA through acetylcarnitine appears key to matching instantaneous acetyl-CoA supply with metabolic demand, thereby helping to balance myocardial substrate supply and contractile function.
Asunto(s)
Acetilcoenzima A/metabolismo , Acetilcarnitina/metabolismo , Carnitina O-Acetiltransferasa/metabolismo , Metabolismo Energético , Espectroscopía de Resonancia Magnética , Miocardio/enzimología , Complejo Piruvato Deshidrogenasa/metabolismo , Animales , Isótopos de Carbono , Ácido Cítrico/metabolismo , Ácido Glutámico/metabolismo , Masculino , Contracción Miocárdica , Oxidación-Reducción , Periodo Posprandial , Ácido Pirúvico/metabolismo , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Short-term consumption of a high-fat diet impairs exercise capacity in both rats and humans, and increases expression of the mitochondrial uncoupling protein, UCP3, in rodent cardiac and skeletal muscle via activation of the transcription factor, peroxisome proliferator-activated receptor α (PPARα). Unlike long-chain fatty acids however, medium-chain fatty acids do not activate PPARα and do not increase muscle UCP3 expression. We therefore investigated exercise performance and cardiac mitochondrial function in rats fed a chow diet (7.5% kcal from fat), a long-chain triglyceride (LCT) rich diet (46% kcal from LCTs) or a medium-chain triglyceride (MCT) rich diet (46% kcal from MCTs). Rats fed the LCT-rich diet for 15 days ran 55% less far than they did at baseline, whereas rats fed the chow or MCT-rich diets neither improved nor worsened in their exercise capacities. Moreover, consumption of an LCT-rich diet increased cardiac UCP3 expression by 35% and decreased oxidative phosphorylation efficiency, whereas consumption of the MCT-rich diet altered neither UCP3 expression nor oxidative phosphorylation efficiency. Our results suggest that the negative effects of short-term high-fat feeding on exercise performance are predominantly mediated by long-chain rather than medium-chain fatty acids, possibly via PPARα-dependent upregulation of UCP3.
RESUMEN
Elevated levels of cardiac mitochondrial uncoupling protein 3 (UCP3) and decreased cardiac efficiency (hydraulic power/oxygen consumption) with abnormal cardiac function occur in obese, diabetic mice. To determine whether cardiac mitochondrial uncoupling occurs in non-genetic obesity, we fed rats a high fat diet (55% kcal from fat) or standard laboratory chow (7% kcal from fat) for 3 weeks, after which we measured cardiac function in vivo using cine MRI, efficiency in isolated working hearts and respiration rates and ADP/O ratios in isolated interfibrillar mitochondria; also, measured were medium chain acyl-CoA dehydrogenase (MCAD) and citrate synthase activities plus uncoupling protein 3 (UCP3), mitochondrial thioesterase 1 (MTE-1), adenine nucleotide translocase (ANT) and ATP synthase protein levels. We found that in vivo cardiac function was the same for all rats, yet oxygen consumption was 19% higher in high fat-fed rat hearts, therefore, efficiency was 21% lower than in controls. We found that mitochondrial fatty acid oxidation rates were 25% higher, and MCAD activity was 23% higher, in hearts from rats fed the high fat diet when compared with controls. Mitochondria from high fat-fed rat hearts had lower ADP/O ratios than controls, indicating increased respiratory uncoupling, which was ameliorated by GDP, a UCP3 inhibitor. Mitochondrial UCP3 and MTE-1 levels were both increased by 20% in high fat-fed rat hearts when compared with controls, with no significant change in ATP synthase or ANT levels, or citrate synthase activity. We conclude that increased cardiac oxygen utilisation, and thereby decreased cardiac efficiency, occurs in non-genetic obesity, which is associated with increased mitochondrial uncoupling due to elevated UCP3 and MTE-1 levels.
Asunto(s)
Dieta/efectos adversos , Mitocondrias/metabolismo , Obesidad/metabolismo , Animales , Ácidos Grasos/efectos adversos , Immunoblotting , Canales Iónicos/metabolismo , Masculino , Proteínas Mitocondriales/metabolismo , Técnicas de Cultivo de Órganos , Oxidación-Reducción/efectos de los fármacos , Consumo de Oxígeno/fisiología , Palmitoil-CoA Hidrolasa , Ratas , Ratas Wistar , Tioléster Hidrolasas/metabolismo , Proteína Desacopladora 3RESUMEN
BACKGROUND: High-fat, low-carbohydrate diets are widely used for weight reduction, but they may also have detrimental effects via increased circulating free fatty acid concentrations. OBJECTIVE: We tested whether raising plasma free fatty acids by using a high-fat, low-carbohydrate diet results in alterations in heart and brain in healthy subjects. DESIGN: Men (n = 16) aged 22 ± 1 y (mean ± SE) were randomly assigned to 5 d of a high-fat, low-carbohydrate diet containing 75 ± 1% of calorie intake through fat consumption or to an isocaloric standard diet providing 23 ± 1% of calorie intake as fat. In a crossover design, subjects undertook the alternate diet after a 2-wk washout period, with results compared after the diet periods. Cardiac (31)P magnetic resonance (MR) spectroscopy and MR imaging, echocardiography, and computerized cognitive tests were used to assess cardiac phosphocreatine (PCr)/ATP, cardiac function, and cognitive function, respectively. RESULTS: Compared with the standard diet, subjects who consumed the high-fat, low-carbohydrate diet had 44% higher plasma free fatty acids (P < 0.05), 9% lower cardiac PCr/ATP (P < 0.01), and no change in cardiac function. Cognitive tests showed impaired attention (P < 0.01), speed (P < 0.001), and mood (P < 0.01) after the high-fat, low-carbohydrate diet. CONCLUSION: Raising plasma free fatty acids decreased myocardial PCr/ATP and reduced cognition, which suggests that a high-fat diet is detrimental to heart and brain in healthy subjects.
Asunto(s)
Cognición/efectos de los fármacos , Grasas de la Dieta/efectos adversos , Metabolismo Energético/efectos de los fármacos , Ácidos Grasos no Esterificados/sangre , Corazón/fisiología , Fosfocreatina/metabolismo , Adenosina Trifosfato/metabolismo , Adulto , Afecto/efectos de los fármacos , Atención/efectos de los fármacos , Estudios Cruzados , Dieta Baja en Carbohidratos/psicología , Carbohidratos de la Dieta/farmacología , Ecocardiografía , Ingestión de Energía , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Valores de Referencia , Adulto JovenRESUMEN
Many diseases of the heart are characterised by changes in substrate utilisation, which is regulated in part by the activity of the enzyme pyruvate dehydrogenase (PDH). Consequently, there is much interest in the in vivo evaluation of PDH activity in a range of physiological and pathological states to obtain information on the metabolic mechanisms of cardiac diseases. Hyperpolarised [1-(13)C]pyruvate, detected using MRS, is a novel technique for the noninvasive evaluation of PDH flux. PDH flux has been assumed to directly reflect in vivo PDH activity, although to date this assumption remains unproven. Control animals and animals undergoing interventions known to modulate PDH activity, namely high fat feeding and dichloroacetate infusion, were used to investigate the relationship between in vivo hyperpolarised MRS measurements of PDH flux and ex vivo measurements of PDH enzyme activity (PDH(a)). Further, the plasma concentrations of pyruvate and other important metabolites were evaluated following pyruvate infusion to assess the metabolic consequences of pyruvate infusion during hyperpolarised MRS experiments. Hyperpolarised MRS measurements of PDH flux correlated significantly with ex vivo measurements of PDH(a), confirming that PDH activity influences directly the in vivo flux of hyperpolarised pyruvate through cardiac PDH. The maximum plasma concentration of pyruvate reached during hyperpolarised MRS experiments was approximately 250 µM, equivalent to physiological pyruvate concentrations reached during exercise or with dietary interventions. The concentrations of other metabolites, including lactate, glucose and ß-hydroxybutyrate, did not vary during the 60 s following pyruvate infusion. Hence, during the 60-s data acquisition period, metabolism was minimally affected by pyruvate infusion.
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Resonancia Magnética Nuclear Biomolecular/métodos , Complejo Piruvato Deshidrogenasa/metabolismo , Animales , Cinética , Masculino , Piruvatos/sangre , Ratas , Ratas Wistar , EspectrofotometríaRESUMEN
We postulated that changes in cardiac high-energy phosphate metabolism may underlie the myocardial dysfunction caused by hypobaric hypoxia. Healthy volunteers (n=14) were studied immediately before, and within 4 d of return from, a 17-d trek to Mt. Everest Base Camp (5300 m). (31)P magnetic resonance (MR) spectroscopy was used to measure cardiac phosphocreatine (PCr)/ATP, and MR imaging and echocardiography were used to assess cardiac volumes, mass, and function. Immediately after returning from Mt. Everest, total body weight had fallen by 3% (P<0.05), but left ventricular mass, adjusted for changes in body surface area, had disproportionately decreased by 11% (P<0.05). Alterations in diastolic function were also observed, with a reduction in peak left ventricular filling rates and mitral inflow E/A, by 17% (P<0.05) and 24% (P<0.01), respectively, with no change in hydration status. Compared with pretrek, cardiac PCr/ATP ratio had decreased by 18% (P<0.01). Whether the abnormalities were even greater at altitude is unknown, but all had returned to pretrek levels after 6 mo. The alterations in cardiac morphology, function, and energetics are similar to findings in patients with chronic hypoxia. Thus, a decrease in cardiac PCr/ATP may be a universal response to periods of sustained low oxygen availability, underlying hypoxia-induced cardiac dysfunction in healthy human heart and in patients with cardiopulmonary diseases.
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Altitud , Metabolismo Energético/fisiología , Ventrículos Cardíacos/anatomía & histología , Miocardio/metabolismo , Función Ventricular/fisiología , Aclimatación , Adulto , Femenino , Humanos , Masculino , Montañismo , Tamaño de los Órganos , Fosfatos/metabolismoRESUMEN
BACKGROUND: T1 mapping allows direct in-vivo quantitation of microscopic changes in the myocardium, providing new diagnostic insights into cardiac disease. Existing methods require long breath holds that are demanding for many cardiac patients. In this work we propose and validate a novel, clinically applicable, pulse sequence for myocardial T1-mapping that is compatible with typical limits for end-expiration breath-holding in patients. MATERIALS AND METHODS: The Shortened MOdified Look-Locker Inversion recovery (ShMOLLI) method uses sequential inversion recovery measurements within a single short breath-hold. Full recovery of the longitudinal magnetisation between sequential inversion pulses is not achieved, but conditional interpretation of samples for reconstruction of T1-maps is used to yield accurate measurements, and this algorithm is implemented directly on the scanner. We performed computer simulations for 100 msAsunto(s)
Técnicas de Imagen Sincronizada Cardíacas
, Frecuencia Cardíaca
, Interpretación de Imagen Asistida por Computador
, Imagen por Resonancia Magnética
, Infarto del Miocardio/patología
, Mecánica Respiratoria
, Adulto
, Algoritmos
, Técnicas de Imagen Sincronizada Cardíacas/instrumentación
, Simulación por Computador
, Medios de Contraste
, Electrocardiografía
, Inglaterra
, Femenino
, Gadolinio DTPA
, Humanos
, Imagen por Resonancia Magnética/instrumentación
, Masculino
, Persona de Mediana Edad
, Infarto del Miocardio/fisiopatología
, Fantasmas de Imagen
, Valor Predictivo de las Pruebas
, Reproducibilidad de los Resultados
, Factores de Tiempo
RESUMEN
Efficiency, defined as the amount of work produced for a given amount of oxygen consumed, is a key determinant of endurance capacity, and can be altered by metabolic substrate supply, in that fatty acid oxidation is less efficient than glucose oxidation. It is unclear, however, whether consumption of a high-fat diet would be detrimental or beneficial for endurance capacity, due to purported glycogen-sparing properties. In addition, a high-fat diet over several months leads to cognitive impairment. Here, we tested the hypothesis that short-term ingestion of a high-fat diet (55% kcal from fat) would impair exercise capacity and cognitive function in rats, compared with a control chow diet (7.5% kcal from fat) via mitochondrial uncoupling and energy deprivation. We found that rats ran 35% less far on a treadmill and showed cognitive impairment in a maze test with 9 d of high-fat feeding, with respiratory uncoupling in skeletal muscle mitochondria, associated with increased uncoupling protein (UCP3) levels. Our results suggest that high-fat feeding, even over short periods of time, alters skeletal muscle UCP3 expression, affecting energy production and physical performance. Optimization of nutrition to maximize the efficiency of mitochondrial ATP production could improve energetics in athletes and patients with metabolic abnormalities.
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Trastornos del Conocimiento/inducido químicamente , Grasas de la Dieta/toxicidad , Resistencia Física/efectos de los fármacos , Animales , Dieta , Metabolismo Energético , Ácidos Grasos/metabolismo , Canales Iónicos/metabolismo , Masculino , Mitocondrias Musculares/metabolismo , Proteínas Mitocondriales/metabolismo , Músculo Esquelético/metabolismo , Palmitoil-CoA Hidrolasa , Ratas , Ratas Wistar , Tioléster Hidrolasas/metabolismo , Factores de Tiempo , Proteína Desacopladora 3RESUMEN
Hyperpolarized (13)C-labeled substrates directly provide a source of magnetic resonance (MR) signal to observe the substrates' real-time uptake and enzymatic conversion. The aim of this study was to optimize the concentration of hyperpolarized [1-(13)C]pyruvate infused as a metabolic tracer, by observing the mitochondrial conversion of pyruvate to H(13)CO(3)(-) in heart tissue. Hyperpolarized pyruvate was infused into rats at concentrations between 20 mM and 80 mM and the relationships between [1-(13)C]lactate, [1-(13)C]alanine, and H(13)CO(3)(-) production and the infused pyruvate concentration were investigated. H(13)CO(3)(-) production reached saturation above 40 mM infused pyruvate concentration, indicating that hyperpolarized MR experiments performed at this concentration maximize the H(13)CO(3)(-) signal with minimal alterations to in vivo substrate composition. Additionally, the linear dependence of alanine production on pyruvate concentration confirmed that hyperpolarized MR methods in the heart reveal enzyme activity, rather than cellular uptake. H(13)CO(3)(-) production demonstrated evidence of sigmoidal enzyme kinetics, a reflection of the allosteric nature of the pyruvate dehydrogenase (PDH) enzyme complex. This protocol could be useful to optimize the infused concentration of other hyperpolarized metabolites in different organs, to ensure adequate MR signal with minimum metabolic perturbation.
Asunto(s)
Alanina/farmacocinética , Isótopos de Carbono/farmacocinética , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Miocardio/metabolismo , Animales , Medios de Contraste/farmacocinética , Corazón/anatomía & histología , Masculino , Tasa de Depuración Metabólica , Radiofármacos/farmacocinética , Ratas , Ratas WistarRESUMEN
The advent of hyperpolarized (13)C magnetic resonance (MR) has provided new potential for the real-time visualization of in vivo metabolic processes. The aim of this work was to use hyperpolarized [1-(13)C]pyruvate as a metabolic tracer to assess noninvasively the flux through the mitochondrial enzyme complex pyruvate dehydrogenase (PDH) in the rat heart, by measuring the production of bicarbonate (H(13)CO(3)(-)), a byproduct of the PDH-catalyzed conversion of [1-(13)C]pyruvate to acetyl-CoA. By noninvasively observing a 74% decrease in H(13)CO(3)(-) production in fasted rats compared with fed controls, we have demonstrated that hyperpolarized (13)C MR is sensitive to physiological perturbations in PDH flux. Further, we evaluated the ability of the hyperpolarized (13)C MR technique to monitor disease progression by examining PDH flux before and 5 days after streptozotocin induction of type 1 diabetes. We detected decreased H(13)CO(3)(-) production with the onset of diabetes that correlated with disease severity. These observations were supported by in vitro investigations of PDH activity as reported in the literature and provided evidence that flux through the PDH enzyme complex can be monitored noninvasively, in vivo, by using hyperpolarized (13)C MR.