Demand creates its own supply: the Na/K‐ATPase controls metabolic reserve and flexibility

Introduction: The adult heart utilizes mostly fat for energy production, with adaptation to different fuels (“metabolic plasticity”) being a hallmark of the healthy heart. However, metabolic maladaptation is known to occur in heart failure. As such, the ability of the heart to metabolize specific substrates could impact the outcome of pathological insults, such as ischemia-reperfusion (IR) injury. The aim of this study was to develop a system whereby adult mouse cardiomyocytes (AMC) subjected to IR injury could be supplied with different fuels, and metabolism measured in real-time. Methods: AMC were divided in 3 groups, supplied either with glucose (GLU, 5mM), palmitate/fat free BSA (FAT, 100µM) or GLU+FAT. A previously developed method for in-vitro IR injury using a Seahorse XF24 [1], was adopted for ACM. IR comprised 60 min. ischemia and 60 min. reperfusion, and additional metabolic parameters were measured separately using mitochondrial inhibitors and uncouplers [2]. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were simultaneously measured during the IR protocol, followed by a cell death assay. Results: FAT cells showed higher baseline OCR and lower ECAR rates compare to GLU cells, although uncoupled OCR was lower in FAT group, suggesting a lower metabolic reserve capacity for cells respiring on fat. Upon IR, the drop in pH was significantly greater in GLU compare to FAT, indicating faster lactate production. During reperfusion, both OCR and ECAR recovered to pre-ischemic levels in GLU cells but failed to do so in FAT cells. Post-IR cell death was significantly higher in FAT vs. GLU. Surprisingly, GLU+FAT (modeling a “physiologic” substrate mix) replicated the same metabolic profile and cell death as GLU. Conclusions: (i) AMC had better recovery from IR injury using glucose as fuel. (ii) Lower cell viability in FAT (vs. GLU) correlated with smaller metabolic reserve capacity and with a smaller pH drop during ischemia. This is consistent with a known protective role for acidification during IR injury. (iii) Mixed substrates (GLU+FAT) gave a similar response to glucose alone, suggesting that fat may not be toxic, rather glucose is protective, in IR injury. [1] Circ Res. (2012), 110. 948-57. [2] J Vis Exp. (2010), 46. pii: 2511.

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Identification of impaired metabolic reserve by atrial pacing in patients with significant coronary artery stenosis.

Circulation ◽

10.1161/01.cir.74.2.281 ◽

1986 ◽

Vol 74 (2) ◽

pp. 281-292 ◽

Cited By ~ 39

Author(s):

M Grover-McKay ◽

H R Schelbert ◽

M Schwaiger ◽

H Sochor ◽

P M Guzy ◽

...

Keyword(s):

Coronary Artery ◽

Coronary Artery Stenosis ◽

Artery Stenosis ◽

Atrial Pacing ◽

Significant Coronary Artery Stenosis ◽

Metabolic Reserve

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Metabolic Reserve as a Determinant of Cognitive Aging

Journal of Alzheimer s Disease ◽

10.3233/jad-2011-110899 ◽

2012 ◽

Vol 30 (s2) ◽

pp. S5-S13 ◽

Cited By ~ 27

Author(s):

Alexis M. Stranahan ◽

Mark P. Mattson

Keyword(s):

Cognitive Aging ◽

Metabolic Reserve

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On the buoyancy of some deep-sea sharks

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1969.0003 ◽

1969 ◽

Vol 171 (1025) ◽

pp. 415-429 ◽

Cited By ~ 47

Keyword(s):

Specific Gravity ◽

Deep Sea ◽

Oil Content ◽

Sea Water ◽

Metabolic Energy ◽

Unit Weight ◽

Cod Liver Oil ◽

Neutral Buoyancy ◽

Temperature And Pressure ◽

Metabolic Reserve

Fish of five species of deep-sea squaloids ( Centrophorus squamosus, Centroscymnus coelolepis, Dalaticis licha, Deania calcea and Etmopterus princeps ) and one-deep sea holocephalan ( Hydrolagus affinis ) were all found to float when brought to the surface and placed in surface or laboratory sea water. However, by taking account of the effects of salinity, temperature and pressure differences between this seawater and that in which the animals lived, it is shown that all these animals must have been very close to neutral buoyancy at the bottom of the sea. Every one of these fish had an enormous oily liver and the lift which this gave almost exactly compensated for the weight in sea water of the rest of the animal. These livers contained large amomits of the hydrocarbon squalene which is not a convenient material to have as a metabolic reserve but which, with its low specific gravity (0.86), is particularly suited to give lift, being 80 % more effective per unit weight for this purpose than cod-liver oil. It is calculated that because of this unusual oil such fish not only obtain the lift needed for neutral buoyancy more economically in terms of the weight of oil required, but also in terms of the metabolic energy which has to be used to provide the oil-store responsible for buoyancy. It is argued that these fish must carefully regulate the oil content of their livers so as always to balance exactly the weight in sea water of their other tissues. The mechanism whereby they do this is not known.

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Matrix Revisited

Circulation Research ◽

10.1161/circresaha.114.301863 ◽

2014 ◽

Vol 114 (4) ◽

pp. 717-729 ◽

Cited By ~ 57

Author(s):

Andrew N. Carley ◽

Heinrich Taegtmeyer ◽

E. Douglas Lewandowski

Keyword(s):

Cellular Response ◽

Contractile Function ◽

Pressure Overload ◽

Metabolic Phenotype ◽

Metabolic Enzyme ◽

Energetic Efficiency ◽

Mitochondrial Matrix ◽

Metabolic Intermediates ◽

Signaling Mechanisms ◽

Metabolic Reserve

Metabolic signaling mechanisms are increasingly recognized to mediate the cellular response to alterations in workload demand, as a consequence of physiological and pathophysiological challenges. Thus, an understanding of the metabolic mechanisms coordinating activity in the cytosol with the energy-providing pathways in the mitochondrial matrix becomes critical for deepening our insights into the pathogenic changes that occur in the stressed cardiomyocyte. Processes that exchange both metabolic intermediates and cations between the cytosol and mitochondria enable transduction of dynamic changes in contractile state to the mitochondrial compartment of the cell. Disruption of such metabolic transduction pathways has severe consequences for the energetic support of contractile function in the heart and is implicated in the pathogenesis of heart failure. Deficiencies in metabolic reserve and impaired metabolic transduction in the cardiomyocyte can result from inherent deficiencies in metabolic phenotype or maladaptive changes in metabolic enzyme expression and regulation in the response to pathogenic stress. This review examines both current and emerging concepts of the functional linkage between the cytosol and the mitochondrial matrix with a specific focus on metabolic reserve and energetic efficiency. These principles of exchange and transport mechanisms across the mitochondrial membrane are reviewed for the failing heart from the perspectives of chronic pressure overload and diabetes mellitus.

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