Selection of fuel for muscle activity

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Muscle can use a variety of fuels:

  • plasma glucose;
  • its own reserves of glycogen;
  • triacylglycerol from plasma lipoproteins;
  • plasma non-esterified fatty acids;
  • plasma ketone bodies;
  • triacylglycerol from adipose tissue reserves within the muscle.

The selection of metabolic fuel depends on both the intensity of work being performed and also whether the individual is in the fed or fasting state.

10.6.1 The effect of work intensity on muscle fuel selection

Skeletal muscle contains two types of fibres:

  • Type I (red muscle) fibres. These are also known as slow-twitch muscle fibres. They are relatively rich in mitochondria and myoglobin (hence their colour), and have a high rate of citric acid cycle metabolism, with a low rate of glycolysis. These are the fibres used mainly in prolonged, relatively moderate, work.
  • Type II (white muscle) fibres. These are also known as fast-twitch fibres. They are relatively poor in mitochondria and myoglobin, and have a high rate of glycolysis. Type IIA fibres also have a high rate of aerobic (citric acid cycle) metabolism, whereas type IIB have a low rate of citric acid cycle activity, and are mainly glycolytic. White muscle fibres are used mainly in high-intensity work of short duration (e.g. sprinting and weight-lifting).

Intense physical activity requires rapid generation of ATP, usually for a relatively short time. Under these conditions substrates and oxygen cannot enter the muscle at an adequate rate to meet the demand, and muscle depends on anaerobic glycolysis of its glycogen reserves. As discussed in section, this leads to the release of lactate into the bloodstream, which is used as a substrate for gluconeogenesis in the liver after the exercise has finished.

Less intense physical activity is often referred to as aerobic exercise, because it involves mainly red muscle fibres (and type IIA white fibres) and there is less accumulation of lactate.

The increased rate of glycolysis for exercise is achieved in three ways:

• As ADP begins to accumulate in muscle, it undergoes a reaction catalysed by adenylate kinase: 2 X ADP ^ ATP + AMP As discussed in section, AMP is a potent activator of phosphofructokinase, reversing the inhibition of this key regulatory enzyme by ATP, and so increasing the rate of glycolysis.

moderate exercise fatty acids fatty acids

triacylglycerol glucose

intense exercise fatty acids


Figure 10.12 Utilization of different metabolic fuels in muscle in moderate and intense exercise.

  • Nerve stimulation of muscle results in an increased cytosolic concentration of calcium ions, and hence activation of calmodulin. Calcium—calmodulin activates glycogen phosphorylase, so increasing the rate of formation of glucose 1-phosphate and providing an increased amount of substrate for glycolysis.
  • Adrenaline, released from the adrenal glands in response to fear or fright, acts on cell-surface receptors, leading to the formation of cAMP, which leads to increased activity of protein kinase and increased activity of glycogen phosphorylase (see Figure 10.6).

In prolonged aerobic exercise at a relatively high intensity (e.g. cross-country or marathon running), muscle glycogen and endogenous triacylglycerol are the major fuels, with a modest contribution from plasma non-esterified fatty acids and glucose (see Figure 10.12). As the exercise continues, and muscle glycogen and triacylglycerol begin to be depleted, so plasma non-esterified fatty acids become more important.

At more moderate levels of exercise (e.g. gentle jogging or walking briskly), plasma non-esterified fatty acids provide the major fuel. This means that, for weight reduction, when the aim is to reduce adipose tissue reserves (section 6.3), relatively prolonged exercise of moderate intensity is more desirable than shorter periods of more intense fatty acids

Figure 10.12 Utilization of different metabolic fuels in muscle in moderate and intense exercise.

exercise. More importantly for overweight people, most of the non-esterified fatty acids that are metabolized in moderate exercise are derived from abdominal rather than subcutaneous adipose tissue (section 6.2.3).

At rest, triacylglycerol from plasma lipoproteins is a significant fuel for muscle, providing 5—10% of the fatty acids for oxidation, but non-esterified fatty acids are more important in exercise.

10.6.2 muscle fuel utilization in the fed and fasting states

Glucose is the main fuel for muscle in the fed state, but in the fasting state glucose is spared for use by the brain and red blood cells; glycogen, fatty acids and ketone bodies are now the main fuels for muscle.

As shown in Figure 10.13, there are five mechanisms involved in the control of glucose utilization by muscle:

Ketone Body Breakdown
Figure 10.13 Control of the utilization of metabolic fuels in muscle.
  • The uptake of glucose into muscle is dependent on insulin, as it is in adipose tissue (section 10.5.1). This means that in the fasting state, when insulin secretion is low, there will be little uptake of glucose into muscle.
  • Hexokinase is inhibited by its product, glucose 6-phosphate. As shown in Figure 5.9, glucose 6-phosphate may arise either as a result of the action of hexokinase on glucose or by isomerization of glucose 1-phosphate from glycogen breakdown. The activity of glycogen phosphorylase is increased in response to glucagon in the fasting state (see Figure 10.6), and the resultant glucose 6-phosphate inhibits utilization of glucose. Because glucose transport in muscle acts by facilitated diffusion followed by metabolic trapping by phosphorylation (section, this inhibition of hexokinase will also reduce glucose uptake.
  • The activity of pyruvate dehydrogenase is reduced in response to increasing concentrations of both NADH and acetyl CoA (section 10.5.2). This means that the oxidation of fatty acids and ketones will inhibit the decarboxylation of pyruvate. Under these conditions, the pyruvate that is formed from muscle glycogen by glycolysis will undergo transamination (section to form alanine. Alanine is exported from muscle and used for gluconeogenesis in the liver (section 5.7 and Problem 9.1). Thus, although muscle cannot directly release glucose from its glycogen reserves (because it lacks glucose 6-phosphatase), muscle glycogen is an indirect source of blood glucose in the fasting state.
  • If alanine accumulates in muscle, it acts as an allosteric inhibitor of pyruvate kinase, so reducing the rate at which pyruvate is formed. This end-product inhibition of pyruvate kinase by alanine is over-ridden by high concentrations of fructose bisphosphate, which acts as a feed-forward activator of pyruvate kinase.
  • ATP is an inhibitor of pyruvate kinase, and at high concentrations acts to inhibit the enzyme. More importantly, ATP acts as an allosteric inhibitor of phosphofructokinase (section This means that, under conditions in which the supply of ATP (which can be regarded as the end-product of all energy-yielding metabolic pathways) is more than adequate to meet requirements, the metabolism of glucose is inhibited. Regulation of fatty acid metabolism in muscle

P-Oxidation of fatty acids is controlled by the uptake of fatty acids into the mitochondria — as discussed in section 5.5.1, this is controlled by the activity of carnitine acyl transferase on the outer mitochondrial membrane, and by the countertransport of acyl-carnitine and free carnitine across the inner mitochondrial membrane.

Carnitine acyl transferase activity is controlled by malonyl CoA. As discussed in section 10.5.2, in liver and adipose tissue this serves to inhibit mitochondrial uptake and P-oxidation of fatty acids when fatty acids are being synthesized in the cytosol. Muscle also has an active acetyl CoA carboxylase, and synthesizes malonyl CoA, although it does not synthesize fatty acids, and muscle carnitine acyl transferase is more sensitive to inhibition by malonyl CoA than is the enzyme in liver and adipose tissue.

Muscle also has malonyl CoA decarboxylase, which acts to decarboxylate malonyl CoA back to acetyl CoA. Acetyl CoA carboxylase and malonyl CoA decarboxylase are regulated in opposite directions by phosphorylation catalysed by a 5'-AMP-dependent protein kinase (which thus reflects the state of ATP reserves in the cell; section Phosphorylation in response to an increase in intracellular 5'-AMP results in:

  • inactivation of acetyl CoA carboxylase;
  • activation of malonyl CoA decarboxylase.

This results in a rapid fall in the concentration of malonyl CoA, so relieving the inhibition of carnitine palmitoyl transferase and permitting mitochondrial uptake and ß-oxidation of fatty acids in response to a fall in ATP, and hence a need for increased energy-yielding metabolism.

In the fed state, there is decreased oxidation of fatty acids in muscle as a result of increased activity of acetyl CoA carboxylase in response to insulin action.

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  • Gemma
    What type of metabolism and fuel (nutrient) does the muscle use when it is?
    9 years ago
    How does a muscle use ketone bodies as fuel?
    8 years ago
  • Sisko
    Which substrate , glucose , maltoseor alanine will make the most ATP?
    8 years ago

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