ATP/ADP concentration ratio

Figure 6.14 An increase in the rate of glucose transport, in response to insulin, which increases the rate of glycolysis. This is achieved by increasing the concentrations of all the intermediates in the pathway, indicated by the arrows adjacent to the intermediates. Insulin, physical activity or a decrease in the ATP/ADP concentration ratio all result in increased rates of glucose transport in skeletal muscle. Insulin increases the rate about fivefold, physical activity about 50-fold.

Figure 6.15 Regulation of the number of glucose transporters in the plasma membrane. The transporter affected is GLUT-4. It is unclear which translocation process is affected by insulin, physical activity or a change in the ATP/ADP concentration ratio. Effects on the translocation from within the cell to the membrane or vice versa are indicated here.

Regulation of glycolysis and gluconeogenesis by ATP/ADP concentration ratio in the liver... 

In addition to the processes described above, there still remains one further process which, at least in some cells or tissues, is required prior to the utilisation of ATP in the cytosol that is, the transport of energy within the cytosol, via a shuttle. The transport of ATP out and ADP into the mitochondrion, via the translocase, results in a high ATP/ ADP concentration ratio in the cytosol. However, a high ratio means that the actual concentration of ADP in the cytosol is low, which could result in slow diffusion of ADP from a site of ATP utilisation back to the inner mitochondrial membrane. If sufficiently slow, it could limit the rate of ATP generation. To overcome this, a process exists that transports energy within the cytosol, not by diffusion of ATP and ADP, but by the diffusion of phosphocreatine and creatine, a process known as the phosphocreatine/creatine shuttle. The reactions involved in the shuttle in muscle help to explain the significance of the process. They are ... 

An increase in the rate of cross-bridge cychng increases force of contraction of muscle, which decreases the cytosolic concentration of ATP and increases that of ADP. This results, via the adenine nucleotide translocase, in a similar change in direction of ATP and ADP concentrations within the mitochondrial matrix (i.e. a decrease in the ATP/ADP concentration ratio). 

Figure 9.25 Control of the Krebs q/cle and myosin-ATPase by direct effects of Ccf ions and the resultant effects on electron transfer and oxidative phosphorylation in muscle. The stimulation of the Krebs cycle by ions results in an increase in the NADH/NAD concentration ratio, which stimulates electron transfer. The stimulation of myosin-ATPase by Ca lowers the ATP/ADP concentration ratio, which also stimulates electron transfer. The Ca ions are released from the sarcoplasmic reticulum in muscle in response to nervous stimulation. In addition, generation of ADP by myosin ATPase increases the ADP concentration, which stimulates the cycle. Note that a lack of oxygen will prevent generation of ATP (Chapter 13).

Regulation is achieved by changes in two factors the cytosolic ion concentration and the ATP/ADP concentration ratio, as follows. 

ATP/ADP concentration ratio A decrease in the ATP/ ADP concentration in the cytosol has the following effects ... 

Inhibition or failure to activate any one of these factors could result in fatigue. The primary change within a muscle fibre that results in fatigue is a decrease in the ATP/ADP concentration ratio. This arises when the demand for ATP by physical activity exceeds the ability of the biochemical processes within the fibre to generate ATP at a sufficient rate to satisfy this demand. The raison d etre for fatigue is to restrict the extent of the physical activity so that the ATP/TYDP ratio does not fall to such low values that sufficient energy cannot be transferred to power processes that are essential to the life of the cell (e.g. maintenance of the ion balance within the cell). Two key questions arise ... 

What is the mechanism(s) by which a fall in the ATP/ ADP concentration ratio leads to fatigue ... 

Interpretation of the type of activity Glycogen content (% of initial content) Concentration ( Xmol/g wet weight) Estimated ATP/ADP concentration ratio... 

These decreases in contents of fuel could account for failure to generate sufficient ATP in the muscle, so that the ATP/ADP concentration ratio decreases markedly (Table 13.12) (Figure 13.23). 

The decrease in ATP/ADP concentration ratio, since it decreases the energy released on hydrolysis of ATP which could decrease two processes that would result directly in fatigue the cross bridge cycle and the Na+/K+ ion ATPase (Figure 13.24). 

Figure 13.24 Two key processes that are affected by decrease in ATP/ADP concentration ratio. A low ATP/ADP concentration ratio reduces the energy that is made available when ATP is hydrolysed to ADP. This can have at least two effects that would result in fatigue ...

Glucose is an essential fuel for the brain and, if the blood concentration falls, uptake by the brain decreases and less fuel is available for ATP generation in the neurones. This results in a decrease in the ATP/ADP concentration ratio. Consequently, less energy is released on ATP hydrolysis, so that less is available for synthesis, transport of neurotransmitter within the nerve and release into the synapse. Hypoglycaemia could, therefore, reduce the effectiveness of neurotransmitters which would reduce stimulation of the motor control pathway. The result would be inhibition of muscle contraction (Figure 13.27). 

Figure 13.27 A possible mechanism by which a low blood glucose level could give rise to central fatigue. A low blood glucose level reduces the rate of glucose utilisation in the brain which decreases the ATP/ADP concentration ratio in the presunaptic neurone. This reduces the energy available for synthesis of neurotransmitters, packaging of neurotransmitter molecules into vesicles and exocytosis of neurotransmitter into synaptic cleft. This decreases electrical activity in postsynaptic neurones and hence in the motor pathway.

Failure of neurones to generate sufficient ATP to maintain the ATP/ADP concentration ratio can lead to sufficient... 

In some cases, death due to disease is caused by necrosis. For example, failure of oxygen supply to some cardiomyo-cytes, after occlusion of an arteriole or artery, will decrease the ATP/ADP concentration ratio in these cells, which will... 

Figure 20.34 A simple representation of the processes of necrosis and apoptosis leading to the death of cells. Necrosis is initiated by a decrease In the ATP/ADP concentration ratio, which slows ion pumps, which leads to cation imbalance (e.g. ca ion entry into the cytosol) and hence intracellular damage, entry of water and lysis which can lead to local inflammation. Apoptosis is initiated by specific extracellular or intracellular factors, which lead to cell shrinkage and disruption into apoptotic bodies which are removed by phagocytes.

The cause of the decreased contractile activity is likely to be due to a decrease in ATP/ADP concentration ratio in the cardiomyocyte, since hydrolysis of ATP now results in less energy being transfered for each molecule of ATP that is hydrolysed. That is, sufficient energy is not available to power the maximum rate of the cross-bridge cycle or power the transport of ions across the plasma membrane (e.g. the Na+/K+ pump or the ion channels). Changes in concentrations of such ions can lead to disturbance of electrical activity that controls the contractions of the fibres. 

In an attempt to maintain the ATP/ADP concentration ratio close to the normal value, the myocardium responds in two ways. The rate of ATP generation is increased and the rate of ATP utilisation is decreased. Indeed it is the decrease in the ATP/ADP concentration ratio that results in metabolic changes (i.e. produces metabolic signals) that increase ATP generation and decrease ATP utilisation in the cardiomyocyte. In fact, one signal has both effects, adenosine (see below). 

The equilibrium is such that, as the ATP/ADP concentration ratio decreases, the AMP concentration increases. The... 

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