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A model of brain circulation and metabolism: NIRS signal changes during physiological challenges.

ABSTRACT: We construct a model of brain circulation and energy metabolism. The model is designed to explain experimental data and predict the response of the circulation and metabolism to a variety of stimuli, in particular, changes in arterial blood pressure, CO(2) levels, O(2) levels, and functional activation. Significant model outputs are predictions about blood flow, metabolic rate, and quantities measurable noninvasively using near-infrared spectroscopy (NIRS), including cerebral blood volume and oxygenation and the redox state of the Cu(A) centre in cytochrome c oxidase. These quantities are now frequently measured in clinical settings; however the relationship between the measurements and the underlying physiological events is in general complex. We anticipate that the model will play an important role in helping to understand the NIRS signals, in particular, the cytochrome signal, which has been hard to interpret. A range of model simulations are presented, and model outputs are compared to published data obtained from both in vivo and in vitro settings. The comparisons are encouraging, showing that the model is able to reproduce observed behaviour in response to various stimuli.

SUBMITTER: Banaji M

PROVIDER: S-EPMC2573000 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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A model of brain circulation and metabolism: NIRS signal changes during physiological challenges.

Banaji Murad M Mallet Alfred A Elwell Clare E CE Nicholls Peter P Cooper Chris E CE

PLoS computational biology 20081107 11

We construct a model of brain circulation and energy metabolism. The model is designed to explain experimental data and predict the response of the circulation and metabolism to a variety of stimuli, in particular, changes in arterial blood pressure, CO(2) levels, O(2) levels, and functional activation. Significant model outputs are predictions about blood flow, metabolic rate, and quantities measurable noninvasively using near-infrared spectroscopy (NIRS), including cerebral blood volume and ox ...[more]

PMID: 18989392

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Project description:BACKGROUND:Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity-induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiological cardiac growth. METHODS:We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart. RESULTS:Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, in the recovered state following exercise adaptation, there was an increase in myocardial phosphofructokinase activity and glycolysis. In mice, cardiac-specific expression of a kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgene (GlycoLo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of GlycoLo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in the heart (GlycoHi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiological cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose-fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. CONCLUSIONS:Exercise-induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.

Dataset Information

A model of brain circulation and metabolism: NIRS signal changes during physiological challenges.

Publications

A model of brain circulation and metabolism: NIRS signal changes during physiological challenges.

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