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Journal ArticleDOI

A simple analysis of the "phosphocreatine shuttle"

01 May 1984-American Journal of Physiology-cell Physiology (American Physiological Society)-Vol. 246, Iss: 5
TL;DR: Experimental results demonstrating the transport aspects of the CK reaction emphasize only one feature of a more general notion of facilitated diffusion by near-equilibrium metabolic reactions and do not per se establish the existence of any physical or functional compartmentation of ATP, ADP, PCr, or creatine.
Abstract: The diffusive mobility of solutes chemically connected by reversible reactions in cells is analyzed as a problem of facilitated diffusion. By this term we mean that the diffusive flux of any substance, X, which is in one metabolic pathway, is effectively increased when it participates in a second and equilibrium reaction with another substance Y because the total flux of X in the pathway is the sum of the fluxes of X and Y. This notion is generalized and is seen to include the familiar enhanced intracellular diffusion of oxygen by oxymyoglobin. In this framework the function of creatine kinase (CK) is seen to have two aspects: 1) phosphocreatine (PCr) via the CK reaction buffers the cellular ATP and ADP concentrations and 2) transport of high-energy phosphates is predominantly in the chemical form of PCr. This predominance of PCr is a consequence of the maintained ATP, ADP, and total creatine levels and of the apparent equilibrium constant of the reaction. Thus experimental results demonstrating the transport aspects of the CK reaction emphasize only one feature of a more general notion of facilitated diffusion by near-equilibrium metabolic reactions and do not per se establish the existence of any physical or functional compartmentation of ATP, ADP, PCr, or creatine. PCr can be a large source for increasing inorganic phosphate levels during contractile activity, possibly as a metabolic regulator. Neither the transport nor buffer aspects can be quantitatively important in cells with small distances between ATP-utilizing and ATP-generating sites, such as is the case with cardiac myofibrils and mitochondria.
Citations
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Journal ArticleDOI
TL;DR: Most of the mechanistic studies of fatigue are on isolated animal tissues, and another major challenge is to use the knowledge generated in these studies to identify the mechanisms of fatigue in intact animals and particularly in human diseases.
Abstract: Repeated, intense use of muscles leads to a decline in performance known as muscle fatigue. Many muscle properties change during fatigue including the action potential, extracellular and intracellular ions, and many intracellular metabolites. A range of mechanisms have been identified that contribute to the decline of performance. The traditional explanation, accumulation of intracellular lactate and hydrogen ions causing impaired function of the contractile proteins, is probably of limited importance in mammals. Alternative explanations that will be considered are the effects of ionic changes on the action potential, failure of SR Ca2+ release by various mechanisms, and the effects of reactive oxygen species. Many different activities lead to fatigue, and an important challenge is to identify the various mechanisms that contribute under different circumstances. Most of the mechanistic studies of fatigue are on isolated animal tissues, and another major challenge is to use the knowledge generated in these studies to identify the mechanisms of fatigue in intact animals and particularly in human diseases.

2,054 citations


Cites background from "A simple analysis of the "phosphocr..."

  • ...Calculations of the consumption and diffusion across myofibrils (assuming that ATP is consumed in the myofibrils and synthesized at mitochondria surrounding the myofibrils) indicate that the gradients of ATP are generally very small (311)....

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Journal ArticleDOI
TL;DR: In the brain, the brain is one of the organs that is particularly sensitive to lack of oxygen and in humans at rest is responsible for 20% of total O2 consumption, even though it accounts for only 2% of the body weight.
Abstract: The importance of A TP as the main source of chemical energy in living matter and its involve­ ment in cellular processes has long been recog­ nized. The primary mechanism whereby higher or­ ganisms, including humans, generate ATP is through mitochondrial oxidative phosphorylation. For the majority of organs, the main metabolic fuel is glucose, which in the presence of oxygen under­ goes complete combustion to CO2 and H20: C6H1206 + 602 � 602 + 6H20 + energy ( 1) The free energy (.:lG) liberated in this exergonic re­ action is partially trapped as ATP in two consecu­ tive processes: glycolysis (cytosol) and oxidative phosphorylation (mitochondria). The first produces 2 mol of ATP per mol of glucose, and the second 36 mol of ATP per mol of glucose. In the latter case, 6 mol of ATP are contributed from the oxidation of 2 mol of NADH generated in the cytosol during gly­ colysis and transferred into the mitochondria indi­ rectly through various \"shuttle\" systems. (In the a-glycerophosphate shuttle, the yield of ATP per NADH is reduced from 3 to 2 because the relevant mitochondrial dehydrogenase is a flavoprotein­ linked enzyme). Thus, oxidative phosphorylation yields 1718 times as much useful energy in the form of ATP as can be obtained from the same amount of glucose by glycolysis alone. It is there­ fore not surprising that limitation of O2 supply pro­ duces very damaging effects on cellular function. The brain is one of the organs that is particularly sensitive to lack of oxygen and in humans at rest is responsible for 20% of total O2 consumption al­ though it accounts for only 2% of the body weight. The role of energy in the maintenance of central

811 citations

Journal ArticleDOI
Adelbert Ames1
TL;DR: It seems probable that the supply of energy may impose a limit on the activity of a neuron under normal conditions, and a number of mechanisms have evolved to reduce activity when energy levels are diminished.

638 citations

Journal ArticleDOI
TL;DR: The data suggest that a dietary-induced increase in muscle total Cr concentration can increase PCr resynthesis during the 2nd min of recovery from intense contraction.
Abstract: Biopsy samples were obtained from the vastus lateralis muscle of eight subjects after 0, 20, 60, and 120 s of recovery from intense electrically evoked isometric contraction. Later (10 days), the same procedures were performed using the other leg, but subjects ingested 20 g creatine (Cr)/day for the preceding 5 days. Muscle ATP, phosphocreatine (PCr), free Cr, and lactate concentrations were measured, and total Cr was calculated as the sum of PCr and free Cr concentrations. In five of the eight subjects, Cr ingestion substantially increased muscle total Cr concentration (mean 29 +/- 3 mmol/kg dry matter, 25 +/- 3%; range 19-35 mmol/kg dry matter, 15-32%) and PCr resynthesis during recovery (mean 19 +/- 4 mmol/kg dry matter, 35 +/- 6%; range 11-28 mmol/kg dry matter, 23-53%). In the remaining three subjects, Cr ingestion had little effect on muscle total Cr concentration, producing increases of 8-9 mmol/kg dry matter (5-7%), and did not increase PCr resynthesis. The data suggest that a dietary-induced increase in muscle total Cr concentration can increase PCr resynthesis during the 2nd min of recovery from intense contraction.

559 citations

References
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Journal ArticleDOI
10 Jan 1980-Nature
TL;DR: The metabolic state of skeletal muscle and brain within intact rats is monitored using high resolution phosphorus nuclear magnetic resonance, indicating the diagnostic possibilities of the method.
Abstract: The metabolic state of skeletal muscle and brain within intact rats is monitored using high resolution phosphorus nuclear magnetic resonance. Regional disturbances in metabolism (for example, localised ischaemia) are easily observed, indicating the diagnostic possibilities of the method. Measurements are made using 'surface' radiofrequency coils, which we discuss in detail.

988 citations

Journal ArticleDOI
TL;DR: Agreement between two highly active enzyme systems in the same compartment is taken as evidence of the existence of near-equilibrium in both these systems and suggests that free cytosolic [sigma ADP] is probably 20-fold lower than measured cell ADP content in mitochondrial-containing tissues.

900 citations

Journal ArticleDOI
30 Jan 1981-Science
TL;DR: It was proposed in 1951 that contracting muscle fibers liberate creatine, which acts to produce an acceptor effect--later called respiratory control--on the muscle mitochondria, which established a molecular basis for a phosphorylcreatine-creatine shuttle for energy transport in heart and skeletal muscle.
Abstract: In order to explain the insulin-like effect of exercise, it was proposed in 1951 that contracting muscle fibers liberate creatine, which acts to produce an acceptor effect--later called respiratory control--on the muscle mitochondria. The development of this notion paralleled the controversy between biochemists and physiologists over the delivery of energy for muscle contraction. With the demonstration of functional compartmentation of creatine kinase on the mitochondrion, it became clear that the actual form of energy transport in the muscle fiber is phosphorylcreatine. The finding of an isoenzyme of creatine phosphokinase attached to the M-line region of the myofibril revealed the peripheral receptor for the mitochondrially generated phosphorylcreatine. This established a molecular basis for a phosphorylcreatine-creatine shuttle for energy transport in heart and skeletal muscle and provided an explanation for the inability to demonstrate experimentally a direct relation between muscle activity and the concentrations of adenosine triphosphate and adenosine diphosphate.

739 citations

Journal ArticleDOI
TL;DR: The observed equilibrium constants (Kobs) of the creatine kinase, myokinase, glucose-6-phosphatase, and fructose-1,6-diph phosphatase reactions have been determined at 38 degrees C, pH 7.0, ionic strength 0.25, and varying free magnesium concentrations.

587 citations