Medical Physiology, 3rd Edition

Conversion of Chemical Energy to Mechanical Work

At rest, skeletal muscle has a low metabolic rate. In response to contractile activity, the energy consumption of skeletal muscle can easily rise >100-fold. The body meets this increased energy demand by mobilizing energy stores both locally from muscle glycogen and triacylglycerols, and systemically from liver glycogen and adipose tissue triacylglycerols. The integrated physiological response to exercise involves the delivery of sufficient O2 and fuel to ensure that the rate of ATP synthesis rises in parallel with the rate of ATP breakdown. Indeed, skeletal muscle precisely regulates the ratio of ATP to ADP even with these large increases in ATP turnover.

Physical performance can be defined in terms of power (work/time), speed, or endurance. Skeletal muscle has three energy systems, each designed to support a particular type of performance (Fig. 60-4). For power events, which typically last a few seconds or less (e.g., hitting a ball with a bat), the immediate energy sources include ATP and phosphocreatine (PCr). For spurts of activity that last several seconds to a minute (e.g., sprinting 100 m), muscles rely primarily on the rapid nonoxidative breakdown of carbohydrate stored as muscle glycogen to form ATP. For activities that last 2 minutes or longer but have low power requirements (e.g., jogging several kilometers), the generation of ATP through the oxidation of fat and glucose derived from the circulation becomes increasingly important. We now consider the key metabolic pathways for producing the energy that enables skeletal muscle to have such a tremendous dynamic range of activity.

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FIGURE 60-4 Energy sources for muscle contraction. (Modified from Edington DW, Edgerton VR: The Biology of Physical Activity. Boston, Houghton Mifflin, 1976.)

ATP and PCr provide immediate but limited energy

At the onset of exercise, or during the transition to a higher intensity of contractile activity, the immediate energy sources are ATP and PCr. As for any other cell, muscle cells break down ATP to ADP and inorganic phosphate (Pi), releasing ~11.5 kcal/mole of free energy (ΔG) under physiological conditions (see p. 1174):

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(60-1)

Muscle cells rapidly regenerate ATP from PCr in a reaction that is catalyzed by creatine kinase:

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(60-2)

Resting skeletal muscle cells contain 5 to 6 mmol/kg of ATP but 25 to 30 mmol/kg of PCr—representing nearly 5-fold more energy. These two energy stores are sufficient to support intense contractile activity for only a few seconds. When rates of ATP breakdown (see Equation 60-1) are high, ADP levels (normally very low) increase and can actually interfere with muscle contraction. Under such conditions, adenylate kinase (also known as myokinase) transfers the second phosphate group from one ADP to another, thereby regenerating ATP:

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(60-3)

The foregoing reaction is limited by the initial pool of ADP, which is small. In contrast, creatine kinase (see Equation 60-2) so effectively buffers ATP that [ATP]i changes very little. Although changes in [ATP]icannot provide an effective signal to stimulate metabolic pathways of energy production, the products of ATP hydrolysis—Pi, ADP, and AMP—are powerful signals.

The high-energy phosphates ATP + PCr are historically referred to as phosphagens and are recognized as the immediate energy supply because they are readily available, albeit for only several seconds (see Fig. 60-4, red curve). This role is of particular importance at the onset of exercise and during transitions to more intense activity, before other metabolic pathways have time to respond.

Anaerobic glycolysis provides a rapid but self-limited source of ATP

When high-intensity exercise continues for more than several seconds, the breakdown of ATP and PCr is followed almost instantly by the accelerated breakdown of intramuscular glycogen to glucose and then to lactate. This anaerobic metabolism of glucose has the major advantage of providing energy quickly to meet the increased metabolic demands of an intense workload, even before O2, glucose, or fatty-acid delivery from blood increases. However, because of the low ATP yield of this pathway, muscle rapidly depletes its glycogen stores, which so that intense activity is limited to durations of ~1 minute (see Fig. 60-4, purple curve).

Muscle fibers store 300 to 400 g of carbohydrate in the form of glycogen (see p. 1171) and, particularly in the case of type II fibers, are rich in the enzymes required for glycogenolysis and glycolysis. In glycogenolysis (see p. 1182), phosphorylase breaks down glycogen to glucose-1-phosphate. Activation of the sympathetic nervous system during exercise elevates levels of epinephrine and—by activating β-adrenergic receptors on muscle fibers—promotes the breakdown of muscle glycogen. Subsequently, phosphoglucomutase converts glucose-1-phosphate to glucose-6-phosphate (G6P). Muscle fibers can also take up blood-borne glucose using GLUT4 transporters (see p. 1047) and use hexokinase to phosphorylate it to G6P. During nonoxidative generation of ATP (see Fig. 60-4, purple curve), intracellular glycogen is more important than blood-borne glucose in rapidly contributing G6P for entry into glycolysis—breakdown of glucose to pyruvate (see Fig. 58-6A).

In the absence of O2, or when glycolysis generates pyruvate more rapidly than the mitochondria can oxidize it (see below), muscle cells can divert pyruvate to lactic acid, which readily dissociates into H+ and lactate. The overall process generates two ATP molecules per glucose molecule:

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(60-4)

This anaerobic regeneration of ATP from ADP through breakdown of intramuscular glycogen, although faster than oxidative metabolism, captures only a fraction of the energy stored in glucose. Moreover, the process is self-limiting because the H+ generated from the dissociation of lactic acid can lower pHi from 7.1 to nearly 6.2; the lower pH inhibits glycolysis and impairs the contractile process, which contributes to muscle fatigue (see p. 1213).

Oxidation of glucose, lactate, and fatty acids provides a slower but long-term source of ATP

The body stores only a small amount of O2 in the blood, and the cardiovascular and respiratory systems require 1 to 2 minutes to increase O2 delivery to muscle to support oxidative metabolism. Endurance training accelerates these adjustments. Nevertheless, before the increase in O2 delivery is complete, skeletal muscle must rely on the immediate release of energy from ATP and PCr, as well as anaerobic glycolysis, as just discussed. As blood flow and O2 delivery increase over the first 1 to 2 minutes, the contribution of aerobic ATP production reduces the dependence on short-term sources of ATP. Thus, in order to sustain light and intermediate physical activity for longer than ~1 minute, muscle regenerates ATP through oxidative metabolism in the mitochondria of type I and type IIa muscle fibers (see Fig. 60-4, blue curve). Muscle also uses oxidative metabolism to recover from intense activities of short duration that relied on the immediate and nonoxidative systems of energy supply.

The nonoxidative metabolism of glucose provides nearly 100-fold more energy than is available via the immediate breakdown of ATP and PCr. However, oxidative metabolism of the same amount of glucose provides 15-fold more energy than the nonoxidative metabolism of glucose.

Oxidation of Nonmuscle Glucose

The aerobic metabolism of glucose, although slower than anaerobic glycolysis (see Equation 60-4), provides nearly 15-fold more ATP molecules per glucose molecule (see Table 58-4): imageN58-15

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(60-5)

The majority of glucose that contracting skeletal muscle oxidizes during aerobic energy production comes from circulating glucose, which in turn originates primarily from the breakdown of the hepatic glycogen stores of 75 to 100 g (see p. 1171). Exercising muscle can increase its uptake of circulating glucose by 7- to 40-fold; this uptake is balanced by enhanced hepatic glucose release, so that blood [glucose] is stabilized. An increase in portal vein levels of glucagon, in particular (see Fig. 51-12), and a decrease in insulin—together with an increase in epinephrine (see Fig. 58-9B)—are the main signals for this elevated hepatic glucose output during exercise.

Contracting skeletal muscle is an important sink for blood-borne glucose (Fig. 60-5). Moreover, contractile activity triggers the translocation of additional GLUT4 transporters (see p. 114) from the cytosol to the plasma membrane. This process, which is insulin independent and is likely mediated by activation of AMP kinase, supports increased glucose uptake. Because exercise-induced translocation of GLUT4 does not depend on insulin, endurance exercise is an important adjunct in controlling elevated levels of blood [glucose] in patients with diabetes.

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FIGURE 60-5 Steady-state energy supply to muscle from energy stores in muscle, liver, and adipose tissue. CoA, coenzyme A.

Oxidation of Lactate

During the first minutes of exercise, active muscle fibers use glycogenolysis to liberate glucose and then use glycolysis to form either pyruvate or lactate, depending on the relative activities of glycolysis and mitochondrial respiration. Indeed, lactate production occurs even in fully aerobic contracting muscles with high oxidative capacity. As blood flow and O2 delivery increase during the initial minutes of the cardiovascular and respiratory adjustments to exercise, types I and IIa oxidative muscle fibers convert lactate back to pyruvate for uptake and subsequent oxidation by the mitochondria. In addition, glycolytic (type IIx) muscle fibers release lactate that can diffuse to nearby oxidative muscle fibers for aerobic production of ATP (see Fig. 60-5). The lactate that escapes into the bloodstream can enter other skeletal muscles or the heart for oxidation (see Fig. 60-5), or the liver for gluconeogenesis (discussed in next paragraph). This shuttling of lactate provides a metabolic link between anaerobic and oxidative cells. After the initial few minutes of moderate-intensity exercise—and after the cardiovascular and respiratory adjustments have stabilized—exercising muscle takes up and oxidizes blood-borne glucose and simultaneously diminishes its release of lactic acid.

Gluconeogenesis

Hepatic gluconeogenesis (see p. 1176) becomes increasingly important as exercise is prolonged beyond an hour and hepatic glycogen stores become depleted. The most important substrates for hepatic gluconeogenesis are lactate and alanine. During prolonged exercise, the key substrate is lactate released into the circulation by contracting skeletal muscle (see below) for uptake by the liver, which resynthesizes glucose for uptake by the muscle—the Cori cycle (see p. 1189).

At workloads exceeding 65% of maximal O2 uptake by the lungs (image; discussed on pages 1213–1214), lactate production rises faster than removal and causes an exponential increase in blood [lactate]. Endurance training increases the rate of lactate clearance from the blood at any given [lactate]. Oxidation is responsible for ~75% of lactate removal, and hepatic gluconeogenesis is responsible for the remainder.

Also during prolonged exercise, the oxidation of branched-chain amino acids by skeletal muscle leads to the release of alanine into the circulation for uptake by the liver, followed by hepatic gluconeogenesis and the release of glucose into the blood for uptake by muscle—the glucose-alanine cycle (see p. 1189).

The Cori and glucose-alanine cycles play an important role in redistributing glycogen from resting muscle to exercising muscle during prolonged exercise and during recovery from exercise. For example, after prolonged arm exercise, lactate release from leg muscle is 6- to 7-fold greater than in the pre-exercise basal state. imageN60-5 Similarly, after leg exercise, lactate release from forearm muscle increases. The signal for this lactate release is the elevated circulating epinephrine level (see p. 1210), which stimulates β-adrenergic receptors in nonexercising muscle as well, leading to glycogen breakdown. Thus, the Cori cycle redistributes glycogen from resting muscle to fuel muscles undergoing prolonged exercise. During recovery, muscle glycogenolysis and lactate release from nonexercising muscle continue, and lactate enters the liver for conversion to glucose, followed by release into the circulation. The subsequent glucose uptake by previously exercising muscles thereby helps to replenish their glycogen stores. In this way, the body ensures an adequate supply of fuel for the next fight-or-flight response.

N60-5

Reallocation of Glycogen from Resting to Exercising Muscle

Contributed by Steven Segal

What is the stimulus for a nonexercising muscle (e.g., leg) to release lactate in response to exercise by another muscle (e.g., arm)? During exercise, enhanced sympathetic nerve activity causes the adrenal medulla to release epinephrine (see p. 583). The degree to which epinephrine release rises depends on exercise intensity, duration, and the mass of muscle engaged in activity. The epinephrine, acting on β2-adrenergic receptors on all (including inactive) muscle fibers, stimulates glycogenolysis. Following the reduction of pyruvate by lactate dehydrogenase, lactate enters the blood (see Fig. 60-5). This effect of circulating epinephrine is the primary reason for the release of lactate from inactive muscle, which contributes to the Cori cycle.

The inactive muscle also releases alanine. One explanation is that, with prolonged physical stress (and certainly with starvation), the release of adrenocorticotropic hormone stimulates the adrenal cortex to release cortisol. In turn, circulating cortisol would enhance proteolysis in all skeletal muscle (see p. 1022), whether active or inactive. The amino acids liberated would include alanine. Probably more significant for exercise is the transamination of pyruvate to alanine as glutamate (derived from other amino acids through the action of transaminases) is converted to α-ketoglutarate (see Fig. 58-13). Thus, whether liberated directly from protein breakdown or synthesized from pyruvate, alanine would enter the circulation. As blood glucose falls and blood alanine rises, the pancreatic α cells release more glucagon, which promotes hepatic gluconeogenesis—the alanine-glucose cycle.

Oxidation of Nonmuscle Lipid

Most stored energy is in the form of triacylglycerols. In the prototypical 70-kg person, adipocytes store ~132,000 kcal of potential energy (see Table 58-1). The mobilization of lipid from adipocytes (see p. 1182) during exercise is largely under the control of the sympathetic nervous system, complemented by the release of growth hormone during exercise lasting >30 to 40 minutes. The result of this mobilization is an increase in circulating levels of fatty acids, which can enter skeletal muscle—especially type I and IIa fibers (see Fig. 60-5).

Not only do fatty acids released from adipocytes enter muscle via the circulation, but skeletal muscle itself stores several thousand kilocalories of potential energy as intracellular triacylglycerols, which contribute to fatty-acid oxidation.

In the presence of adequate O2, fatty acids provide up to 60% of the oxidized fuel supply of muscle during prolonged exercise. The oxidation of fatty acids (see pp. 1183–1185), such as palmitate in the following example, has a very high yield of ATP:

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(60-6)

Lipids are an important source of energy when O2 is available; that is, during prolonged low- to moderate-intensity activity and during recovery following exercise.

Choice of Fuel Sources

For sustained activity of moderate intensity, fat is the preferred substrate, given ample O2 availability. For example, at 50% of image, fatty-acid oxidation accounts for more than half of muscle energy production, with glucose accounting for the remainder. As the duration of exercise further lengthens, glucose utilization progressively declines and fatty-acid oxidation increases, with fatty acids becoming the dominant oxidative fuel. However, as exercise intensity increases, active muscle relies increasingly on glucose derived from intramuscular glycogen as well as on blood-borne glucose. This crossover from lipid to carbohydrate metabolism has the advantage that, per liter of O2 consumed, carbohydrate provides slightly more energy than lipid (see p. 1187). Conversely, as muscle depletes its glycogen stores, it loses its ability to consume O2 at high rates.

At a given metabolic demand, the increased availability and utilization of fatty acids translate to lower rates of glucose oxidation and muscle glycogenolysis, which prolongs the ability to sustain activity. Endurance training promotes these adaptations of skeletal muscle by increasing capillarity (which promotes O2 delivery) and mitochondrial content (which promotes oxidative ATP production). Under conditions of carbohydrate deprivation (e.g., starvation), extremely prolonged exercise (e.g., ultramarathon), and impaired glucose utilization (e.g., diabetes), muscle can also oxidize ketone bodies as their plasma levels rise.