Fig. 4.12 Energy (ATP) generation in skeletal muscle. Only major pathways are shown: each arrow may represent one or more steps in a pathway. The major sites of regulation are shown: a plus sign indicates stimulation. FAT(P) represents a possible fatty acid transporter but it is not clear which might be most important in skeletal muscle (see Table 2.4). It is also possible that fatty acids released by lipoprotein lipase (LPL) (situated in the capillaries) might be transported into the cell by this means. TAG, triacylglycerol; TCA cycle, tricarboxylic acid (Krebs) cycle. The way in which muscle contraction is coordinated with metabolism is discussed in Section 8.4.3.
Glucose uptake is mainly mediated by the insulin-sensitive glucose transporter, GLUT4 (see Box 2.2). GLUT1 is also expressed in skeletal muscle and may play a role in uptake of a glucose at a 'basal' rate. Glucose uptake by GLUT4 has certain characteristics which are relevant. The Km is within the physiological range of plasma glucose concentrations. In the presence of low concentrations of insulin the maximal activity (Vmax) of glucose uptake is low. Raising the insulin concentration brings more transporters into action at the cell membrane (see Fig. 2.5), and hence increases the V . Insulin thus increases the rate at which
° '3 max muscle takes up glucose from the blood. This glucose may be used for glycogen synthesis or metabolism via the pathway of glycolysis.
As in the liver, insulin stimulates the enzyme glycogen synthase in muscle, and inhibits the enzyme glycogen phosphorylase. Thus, when the plasma in sulin concentration is high after a meal, glucose will be stored as glycogen in skeletal muscle. However, the isoforms of the enzymes for glycogen metabolism expressed in muscle have some different regulatory properties from those in the liver. Muscle glycogen synthase has sites that can be phosphorylated by protein kinase-A, which are lacking in the liver isoform. This would give adrenaline a particular ability (acting through cAMP and PKA) to switch off glycogen synthesis in muscle whilst stimulating glycogen breakdown by the means described for the liver (Box 4.1). In addition, muscle glycogen phosphorylase is allosteri-cally activated by AMP and inhibited by glucose 6-phosphate. These will play a role in stimulating glycogen breakdown when the energy status of the muscle cell is low (use of ATP for contraction will be accompanied by some conversion to AMP). In skeletal muscle, there is also a specific mechanism (not understood) for stimulation of glycogen synthesis after exercise when the glycogen store has been depleted. This will be illustrated later (Section 8.4.7).
Fatty acids are also taken up by muscle, particularly in the oxidative fibres. These are either the plasma non-esterified fatty acids, which have arisen from stored triacylglycerol in adipose tissue, or fatty acids carried as triacylglycerol in lipoprotein particles.
It is probable that non-esterified fatty acids are taken up across the cell membrane by a specific transport mechanism (Table 2.4). The activity of the transporter may be regulated as discussed in Section 220.127.116.11, for instance with recruitment of FAT/CD36 to the cell membrane during exercise. However, under resting conditions the rate of fatty acid uptake is usually closely related to the concentration of non-esterified fatty acids in the plasma. Similarly, within the cell fatty acids are oxidised in accordance with their rate of uptake. During exercise there is clearly a need to increase the rate of delivery of substrates for oxidation. In the case of fatty acids, this is brought about by increasing the rate of blood flow through muscle (the rate of delivery from adipose tissue is also increased; see Section 18.104.22.168 below). The rate at which blood flows through any particular muscle increases several-fold when that muscle is exercising, resulting in the delivery of more fatty acids to the muscle. Experiments with perfused muscle preparations in which the delivery of fatty acids is altered either by altering their concentration or by altering the blood flow show that the rate of fatty acid uptake is largely determined by the delivery rate (i.e. blood flow x concentration).
Apart from the situation of exercise, increased uptake of fatty acids by muscle will occur when the plasma non-esterified fatty acid concentration is raised - for instance, during fasting. Under these conditions the muscle will not need to use so much glucose. Mechanisms by which the use of one fuel is regulated in response to the availability of another will be considered again in a later section (Section 6.4). However, one mechanism by which this is achieved in muscle has already been described above, for the liver. This is the inhibition of fatty acid oxidation when glucose utilisation is stimulated, via the effect of malonyl-CoA on CPT-1. It should be noted that skeletal muscle does not express fatty acid synthase, so there is no pathway of fatty acid synthesis: but it does express acetyl-CoA carboxylase to produce malonyl-CoA. Since this is not required for fatty acid synthesis, we have to conclude that it is produced solely in order to regulate the rate of fatty acid oxidation. The isoform of CPT-1 expressed in muscle is actually more sensitive to inhibition by malonyl-CoA than is the liver isoform. In addition, there are two isoforms of acetyl-CoA carboxylase, ACC1 and ACC2 (sometimes called a and P). The ACC1 isoform is generally expressed in tissues where there is an active pathway of fatty acid synthesis such as liver and adipose tissue, so we may imagine that it is feeding malonyl-CoA into this pathway. The ACC2 isoform is expressed more in tissues such as skeletal muscle, where the role of the malonyl-CoA that it produces must be purely regulatory. ACC1 is a cytosolic enzyme, whereas ACC2 is associated with mitochondria, in keeping with its role in providing malonyl-CoA to regulate CPT-1. In skeletal muscle this mechanism would presumably restrict fatty acid oxidation during the period after a meal when glucose and insulin levels are high, and it may be that it then diverts fatty acids into triacylglycerol synthesis.
Plasma triacylglycerol cannot be taken up directly. The fatty acids must first be released by the action of an enzyme, lipoprotein lipase, which is present in the capillaries. This process is therefore similar to the absorption of triacylglycerol from the intestine, and indeed lipoprotein lipase and pancreatic lipase belong to the same family of lipolytic enzymes. Lipoprotein lipase is also present in other tissues, especially adipose tissue. Since more is known about its action in adipose tissue, it will be described in more detail in a later section (Section 22.214.171.124; Fig. 4.15). The fatty acids it releases from triacylglycerol in the capillaries enter the muscle cells, probably by the same means as do plasma non-esterified fatty acids. Thereafter their fate may be either oxidation or re-esterification to replenish the muscle triacylglycerol store.
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Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...