Medical Physiology A Cellular and Molecular Approach, Updated 2nd Ed.


Steven S. Segal

Physical exercise is often the greatest stress that the body encounters in the course of daily life. Skeletal muscle typically accounts for 30% to 50% of the total body mass. Thus, with each bout of muscular activity, the body must make rapid, integrated adjustments at the level of cells and organ systems—and must modulate these adjustments over time. The subdiscipline of exercise physiology and sports science focuses on the integrated responses that enable the conversion of chemical energy into mechanical work. To understand these interdependent processes, one must appreciate where regulation occurs, the factors that limit performance, and the adaptations that occur with repetitive use.

The cross-bridge cycle that underlies contraction of skeletal muscle requires energy in the form of ATP (see Chapter 9). To supply this energy, skeletal muscle converts ~25% of the energy stored in foodstuffs into mechanical work. The rest appears as heat as a result of the inefficiencies of the biochemical reactions (see Chapter 58). Thus, the dissipation of this heat is central to cardiovascular function, fluid balance, and the ability to sustain physical effort—an example of an integrated organ system response. Moreover, because muscle stores of ATP, phosphocreatine (PCr), and glycogen are limited, the ability to sustain physical activity requires another set of integrated cellular and organ system responses to supply O2 and energy sources to active muscles.


In Chapter 9, the cellular and molecular physiology of skeletal muscle contraction is discussed. In this major section, we examine the way in which these smaller elements integrate into a contracting whole muscle.

The motor unit is the functional element of muscle contraction

A typical skeletal muscle receives innervation from ~100 somatic motor neurons. The motor unit consists of a single motor neuron and all the muscle fibers that it activates.

When the motor neuron generates an action potential, all the fibers in the motor unit fire simultaneously. Thus, the fineness of control for movement varies with the innervation ratio—the number of muscle fibers per motor neuron. As discussed later, the small motor units that are recruited during sustained activity contain a high proportion of type I muscle fibers, which are highly oxidative and resistant to fatigue. In contrast, the large motor units that are recruited for brief periods—for rapid, powerful activity—typically consist of type IIa and IIb (see Chapter 9) muscle fibers, which are glycolytic and are much more susceptible to fatigue. (See Note: Innervation Ratio)

Within a whole muscle, muscle fibers of each motor unit intermingle with those of other motor units so extensively that—in a volume of muscle that contains 100 muscle fibers—nerve endings from perhaps 50 different motor neurons synapse on the 100 end plates. Within some muscles, the fibers of a motor unit are constrained to discrete compartments. This anatomical organization enables different regions of a muscle to exert force in somewhat different directions, thereby enabling more precise control of movement.

Muscle force rises with the recruitment of motor units and an increase in their firing frequency

During contraction, the force exerted by a muscle depends on (1) how many motor units are recruited and (2) how frequently each of the active motor neurons fire action potentials. Motor units are recruited in a progressive order, from the smallest (i.e., fewest number of muscle fibers) and therefore the weakest motor units to the largest and strongest. This intrinsic behavior of motor unit recruitment is known as the size principle and reflects inherent differences in the biophysical properties of respective motor neurons. For a given amount of excitatory input (i.e., depolarizing synaptic current; Isyn in Fig. 60-1), a neuronal cell body with smaller volume and surface area has a higher membrane input resistance. Therefore, the depolarizing voltage in a neuron with a smaller neuronal cell body rises to threshold more quickly than in a neuron with a larger cell body (Fig. 60-1). Because the neurons with the small cell bodies tend to innervate a small number of slow-twitch (type I) muscle fibers, the motor units with the greatest resistance to fatigue are the first to be recruited. Conversely, the neurons with the larger cell bodies tend to innervate a larger number of fast-twitch (type II) fibers, so the largest and most fatigable motor units are the last to be recruited. Because the relative timing of action potentials in different motor units is asynchronous, the force developed by individual motor units integrates into a smooth contraction. As a muscle relaxes, the firing of respective motor units diminishes in reverse order.


Figure 60-1 The size principle for motor units. Small motor neurons are more excitable, conduct action potentials more slowly, and excite fewer fibers that tend to be slow twitch (type I). Conversely, large motor neurons are less excitable, conduct action potentials more rapidly, and excite many fibers that tend to be fast twitch (type II). EPSP, excitatory postsynaptic potential. Isyn, depolarizing synaptic current; Vm, membrane potential. (Adapted from Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th ed. New York: McGraw-Hill, 2000.)

At levels of force production lower than the upper limit of recruitment, gradations in force are accomplished through concurrent changes in the number of active motor units and the firing rate of those that have been recruited—rate coding. Once all the motor units in a muscle have been recruited, any further increase in force results from an increase in firing rate. The relative contribution of motor unit recruitment and rate coding varies among muscles. In some cases, recruitment is maximal by the time muscle force reaches ~50% of maximum, whereas in others, recruitment continues until the muscle reaches nearly 90% of maximal force.

In addition to the intrinsic membrane properties of motor neurons (i.e., the size principle), other neurons that originate in the brainstem project to the motor neurons and release the neuromodulatory neurotransmitters serotonin and norepinephrine (see Fig. 13-6). For example, this neuromodulatory input, acting on the motor neurons of small, slow-twitch motor units, can promote self-sustained levels of firing of the motor neurons during the maintenance of posture. In contrast, the withdrawal of this excitatory neuromodulatory input during sleep promotes muscle relaxation. Thus, the brain can control the overall gain of a pool of motor neurons.

Compared with type I motor units, type IIb units are faster and stronger but more fatigable

Within a given motor unit, each muscle fiber is of the same functional type. As summarized in Tables 9-1 and 9-2, the three muscle fiber types—type I, type IIa, and type IIb—differ in contractile and regulatory proteins, the content of myoglobin (and thus color) and mitochondria and glycogen, and the metabolic pathways used to generate ATP (i.e., oxidative versus glycolytic metabolism). These biochemical properties determine a range of functional parameters, including (1) speeds of contraction and relaxation, (2) maximal force, and (3) susceptibility to fatigue (Fig. 60-2).


Figure 60-2 A to C, Properties of fiber types (i.e., motor units in gastrocnemius muscle). The top row shows the tension developed during single twitches for each of the muscle types; the arrows indicate the time of the electrical stimulus. The middle row shows the tension developed during an unfused tetanus at the indicated stimulus frequency (pps, pulses per second). The bottom row shows the degree to which each of the fiber types can sustain force during continuous stimulation. The time scales become progressively larger from the top to bottom rows, with a break in the bottom row. In addition, the tension scales become progressively larger from left (fewer fibers per motor unit) to right (more fibers per motor unit). (Data from Burke RE, Levine DN, Tsairis P, et al. J Physiol 1977; 234:723–748.)

In response to an action potential evoked through the motor axon, slow-twitch (type I) motor units (top row of Fig. 60-2A) require relatively long times to develop tension and return to rest. In contrast, fast-twitch (types IIa and IIb) motor units exhibit relatively short contraction and relaxation times (top row of Fig. 60-2B, C). Accordingly, during repetitive stimulation (middle row of Fig. 60-2), slow-twitch motor units summate to a fused tetanus at lower stimulation frequencies than do fast-twitch motor units. Indeed, the α motor neurons in the spinal cord that drive slow motor units fire at frequencies of 10 to 50 Hz, whereas those that drive fast motor units fire at frequencies ranging from 30 Hz to more than 100 Hz.

The maximal force that can develop per cross-sectional area of muscle tissue is constant across fiber types (~25 N/cm2). Therefore, the ability of different motor units to develop active force is directly proportional to the number and diameter of fibers each motor unit contains. In accord with the innervation ratios of motor units, peak force production (middle row of Fig. 60-2) increases from type I motor units (used for fine control of movement) to type II motor units (recruited during more intense activities).

The susceptibility to fatigue of a motor unit depends on the metabolic profile of its muscle fibers. The red type I muscle fibers have greater mitochondria content and can rely largely on the aerobic metabolism of sugars and lipid for energy because they are well supplied with capillaries for delivery of O2 and nutrients. Type I motor units, although smaller in size (and innervation ratio), are recruited during sustained activity of moderate intensity and are highly resistant to fatigue (bottom row of Fig. 60-2A). In contrast, the larger type II motor units are recruited less often—during brief periods of intense activity—and rely to a greater extent on short-term energy stores (e.g., glycogen stored within the muscle fiber). Among type II motor units, type IIa motor units have a greater mitochondrial content, a larger capacity for aerobic energy metabolism, a greater O2 supply, and a higher endurance capacity and hence are classified as fast fatigue-resistant units (bottom row of Fig. 60-2B). In contrast, type IIb motor units have greater capacity for rapid energy production through nonoxidative (i.e., anaerobic) glycolysis, so they can produce rapid and powerful contractions. However, type IIb units tire more rapidly and are therefore classified as fast fatigable units (bottom row of Fig. 60-2C).

As external forces stretch muscle, series elastic elements contribute a larger fraction of total tension

As sarcomeres contract, some of their force acts laterally—through membrane-associated and transmembrane proteins—on the extracellular matrix and connective tissue that surrounds each muscle fiber. Ultimately, the force is transmitted to bone, typically (but not always) through a tendinous insertion. The structural elements that transmit force from the cross-bridges to the skeleton comprise the series elastic elements of the muscle and behave as a spring with a characteristic stiffness. Stretching resting muscle causes passive tension to increase exponentially with length (see Fig. 9-9C). Thus, muscle stiffness increases with length. During an isometric contraction (see Chapter 9), when the external length of a muscle (or muscle fiber) is held constant, the sarcomeres shorten at the expense of stretching the series elastic elements. An isometric contraction can occur at modest levels of force development, such as holding a cup of coffee, as well as during maximal force development, such as when opposing wrestlers push and pull against each other, with neither gaining ground. Physical activity typically involves contractions in which muscles are shortening and lengthening, as well as periods during which muscle fibers are contracting isometrically.

During cyclic activity such as running, muscles undergo a stretch-shorten cycle that may increase total tension while decreasing active tension. For example, as the calf muscles relax as the foot lands and decelerates, the series elastic elements of the calf muscles (e.g., the Achilles tendon, connective tissue within muscles) are stretched and develop increased passive tension (see Fig. 9-9C). Thus, when the calf muscles contract to begin the next cycle, they start from a higher passive tension and thus use a smaller increment in active tension to reach a higher total tension. This increased force helps to propel the runner forward. (See Note: Effect of Stretch on the Active Tension of Skeletal Muscle)

In a concentric contraction (e.g., climbing stairs), the force developed by the cross-bridges exceeds the external load, and the sarcomeres shorten. During a concentric contraction, a muscle performs positive work (force × distance) and produces power (work/time; see Chapter 9). As shown in Figure 9-9E, the muscle achieves peak power at relatively moderate loads (30% to 40% of isometric tension) and velocities (30% to 40% of maximum shortening velocity). The capacity of a muscle to perform positive work determines physical performance. For example, a stronger muscle can shorten more rapidly against a given load, and a muscle that is metabolically adapted to a particular activity can sustain performance for a longer period of time before it succumbs to fatigue.

In an eccentric contraction (e.g., descending stairs), the force developed by the cross-bridges is less than the imposed load, and the sarcomeres lengthen. During an eccentric contraction, the muscle performs negative work, thus providing a brake to decelerate the applied force being applied, and absorbs power. Eccentric contractions can occur with light loads, such as lowering a cup of coffee to the table, as well as with much heavier loads, such as decelerating after jumping off a bench onto the floor. At the same absolute level of total force production, eccentric contractions—with increasingly stretched sarcomeres—develop less active tension than do concentric or isometric contractions. Conversely, the passive tension developed by the series elastic elements make a greater contribution to total tension. As a result, the tension generated eccentrically is greater than that generated isometrically. When the external force stretches the muscle sufficiently, all the tension is passive, and the limit is the breaking point (see Fig. 19-9B) of the series elastic elements. Thus, eccentric contractions are much more likely than isometric or isotonic contractions to damage muscle fibers and connective tissue.

The action of a muscle depends on the axis of its fibers and its origin and insertion on the skeleton

In addition to the contractile and metabolic properties of muscle fibers discussed earlier, two anatomical features determine the characteristics of the force produced by a muscle. The first anatomical determinant of muscle function is the arrangement of fibers with respect to the axis of force production (i.e., the angle of pennation). With other determinants of performance (e.g., fiber type and muscle mass) being equal, muscles that have a relatively small number of long fibers oriented parallel to the axis of shortening (e.g. the sartorius muscle of the thigh, Fig. 60-3A, top) shorten more rapidly. Indeed, the more sarcomeres are arranged in series, the more rapidly the two ends of the muscle will approach each other. In contrast, muscles that have many short fibers at an angle to the axis (e.g. the soleus muscle of the calf, Fig. 60-3A, bottom) develop more force. Indeed, the greater the number of fibers (and sarcomeres) in parallel with each other, the greater is the total cross-sectional area for developing force.


Figure 60-3 A and B, Determinants of the mechanical action of a muscle.

The second anatomical determinant of limb movement consists of the locations of the origin and insertion of the muscle to the skeleton. Consider, for example, the action of the brachialis muscle on the elbow joint. The distance between the insertion of the muscle on the ulna and the joint’s center of rotation is D, which may be 5 cm. The torque that the muscle produces on the joint is the component of total muscle force that is perpendicular to the ulna, multiplied by D (Fig. 60-3B). An equivalent definition is that torque is the product of the total muscle force multiplied by the moment arm, which is the length of the line segment that runs perpendicular to the muscle and through the center of rotation (Fig. 60-3B). As we flex our elbow, the moment arm is constantly changing, and muscle force changes as well. For this joint, we achieve maximum torque at 60 degrees of flexion.

Fluid and energetically efficient movements require learning

To perform a desired movement—whether playing the piano or serving a tennis ball—the nervous system must activate a combination of muscles with the appropriate contractile properties, recruit motor units in defined patterns, and thereby create suitable mechanical interactions among body segments. When we perform movements with uncertainty—as in learning a new skill—actions tend to be stiff because of concurrent recruitment of motor units in antagonistic muscles that produce force in opposite directions. Such superfluous muscle fiber activity also increases the energy requirements for the activity. Even in someone who is skilled, the fatigue of small motor units leads to the recruitment of larger motor units in the attempt to maintain activity, but with loss of fine control and greater energy expenditure. With learning, recruitment patterns become refined and coordinated, and muscle fibers adapt to the task. Thus, movements become fluid and more energetically efficient, as exemplified by highly trained musicians and athletes who can make difficult maneuvers appear almost effortless.

Strength versus endurance training differentially alters the properties of motor units

The firing pattern of the α motor neuron—over time—ultimately determines the contractile and metabolic properties of the muscle fibers in the corresponding motor unit. This principle was demonstrated elegantly by classic experiments in which the motor nerve to a muscle consisting primarily of fast motor units was cut and switched with that of a muscle consisting primarily of slow motor units. As the axons regenerated and the muscles recovered contractile function over several weeks, the fast muscle became progressively slower and more fatigue resistant, whereas the slow muscle became faster and more susceptible to fatigue. Varying the pattern of efferent nerve impulses through chronic stimulation of implanted electrodes elicits similar changes in muscle properties. A corollary of this principle is that physical activity leads to adaptation only in those motor units that are actually recruited during the activity.

The effects of physical activity on motor unit physiology depend on the intensity and duration of the exercise. In general, sustained periods of low to moderate intensity performed several times per week—endurance training—result in a greater oxidative capacity of muscle fibers and are manifested by increases in O2 delivery, capillary supply, and mitochondrial content. These adaptations reduce the susceptibility of the affected muscle fibers to fatigue. The lean and slender build of long-distance runners reflects highly oxidative muscle fibers of relatively small diameter that promote O2 and CO2 diffusion between capillaries and mitochondria for high levels of aerobic energy production. Further, the high ratio of surface area to volume of the slender body also facilitates cooling of the body during prolonged activity and in hot environments.

In contrast, brief sets of high-intensity contractions performed several times per week—strength training—result in motor units that can produce more force and can shorten against a given load at greater velocity by increasing the amount of contractile protein. The hypertrophied muscles of sprinters and weight lifters exemplify this type of adaptation, which relies more on rapid, anaerobic sources of energy production.


At rest, skeletal muscle has a low metabolic rate. In response to contractile activity, the energy consumption of skeletal muscle can easily rise more than 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 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. Next I consider the key metabolic pathways for producing the energy that enables skeletal muscle to have such a tremendous dynamic range of activity.


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 phosphocreatine 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) and release ~11.5 kcal/mol of free energy (ΔG) under physiological conditions:


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


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 only for a few seconds. When rates of ATP breakdown (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 and thereby regenerates ATP:


The foregoing reaction is limited by the initial pool of ADP, which is small. In contrast, creatine kinase (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 (Fig. 60-4). 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 and thereby limits intense activity to durations of ~1 minute (Fig. 60-4).

Muscle fibers store 300 to 400 g of carbohydrate in the form of glycogen and, particularly in the case of type II fibers, are rich in the enzymes required for glycogenolysis and glycolysis. In glycogenolysis, phosphorylase breaks down glycogen to glucose-1-phosphate. Activation of the sympathetic nervous system during exercise elevates levels of epinephrine and 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 the GLUT4 transporter (see Chapter 58) and use hexokinase to phosphorylate it to G6P. Intracellular glycogen is more important than blood-borne glucose in rapidly contributing G6P for entry into glycolysis—breakdown of glucose to pyruvate (see Fig. 59-6A).

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


This anaerobic regeneration of ATP 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, a process that inhibits glycolysis, impairs the contractile process, and thereby contributes to muscle fatigue.

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 speeds these adjustments. Nevertheless, before the increase in O2 delivery is complete, muscle must rely on the immediate release of energy from ATP and PCr, as well as anaerobic glycolysis, as just discussed. To sustain light and intermediate physical activity for more than ~1 minute, muscle regenerates ATP through oxidative metabolism in the mitochondria of type I and type IIa muscle fibers (Fig. 60-4). Muscle also uses oxidative metabolism to recover from intense activities of short duration that relied on the immediate and anaerobic systems of energy supply.

The anaerobic metabolism of glucose provides nearly 100-fold more energy than is available through the immediate breakdown of ATP and PCr. Oxidative metabolism of glucose, lactate, and fat provides far more than even the anaerobic metabolism of glucose.

Oxidation of Non-Muscle Glucose The aerobic metabolism of glucose, although slower than anaerobic glycolysis (Equation 60-4), provides nearly 15-fold more ATP molecules per glucose (see Table 58-4): (See Note: Shuttle Systems for Moving Reducing Equivalents)


The glucose that muscle oxidizes comes from the breakdown of hepatic glycogen stores of 75 to 100 g. Glucose uptake by exercising muscle can increase 7- to 40-fold above rest. However, increased glucose release from liver (through glycogenolysis) balances the glucose uptake from the blood by active muscle, thereby stabilizing blood [glucose]. 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—are the main signals for this elevated hepatic glucose output during exercise. However, hepatic denervation in dogs does not prevent accelerated rates of glucose production during exercise, a finding showing that sympathetic innervation of the liver is not essential.

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 Chapter 51) 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 is insulin independent, endurance exercise is an important adjunct in controlling elevated levels of blood [glucose] in patients with diabetes.


Figure 60-5 Steady-state energy supply to muscle from energy stores in muscle, liver, and adipose tissue.

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, muscle fibers convert accumulated lactate back to pyruvate for uptake and subsequent oxidation by the mitochondria. In addition, glycolytic (type IIb) muscle fibers release lactate that can diffuse to nearby oxidative muscle fibers (type I and IIa), which can oxidize it (Fig. 60-5). The lactate that escapes into the bloodstream can enter the heart for oxidation, the distant skeletal muscles for oxidation (Fig. 60-5), or the liver for gluconeogenesis (discussed later). This shuttling of lactate provides a link between anaerobic and oxidative cells. After the initial few minutes of moderate-intensity exercise—and after the cardiovascular and respiratory adjustments—exercising muscle takes up and oxidizes blood-borne glucose and simultaneously diminishes its release of lactic acid.

Gluconeogenesis Hepatic gluconeogenesis 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 later) for uptake by the liver, which resynthesizes glucose for uptake by the muscle—the Cori cycle (see Fig. 58-13 and 60-5).

At workloads exceeding 65% of maximal O2 uptake by the lungs (imageO2max), 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 Fig. 58-13).

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. Conversely, after leg exercise, lactate release from forearm muscle increases. Thus, the Cori cycle redistributes glycogen from resting muscle to fuel muscles undergoing prolonged exercise. During recovery, muscle glycogenolysis and lactate release from previously resting muscle continue, and lactate enters the liver for conversion to glucose and release. The subsequent glucose uptake by previously exercising muscles thereby replenishes their glycogen stores. In this way, the body ensures an adequate supply of fuel for the next fight or flight response. (See Note: Reallocation of Glycogen from Resting to Exercising Muscle)

Oxidation of Non-Muscle Lipid Most stored energy is in the form of triglycerides. In the prototypic 70-kg person, adipocytes store ~132,000 kcal of potential energy. The mobilization of lipid from adipocytes during exercise is largely under the control of the sympathetic nervous system, complemented by the release of growth hormone during exercise lasting longer than 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 fibers (Fig. 60-5). In addition to fatty acids that enter muscle from adipocytes, skeletal muscle itself stores ~8000 kcal of potential energy as intracellular triacylglycerols, which contribute to fatty acid oxidation, particularly during recovery following prolonged exertion.

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, using palmitate as an example, has a very high yield of ATP:


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 imageO2max, fatty acid oxidation accounts for more than half of muscle energy production, and glucose accounts for the remainder. As the duration of exercise further lengthens, fatty acid oxidation progressively increases, and it becomes the dominant oxidative fuel as glucose utilization by the muscle declines. 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. 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, thereby prolonging the ability to sustain activity. Endurance training promotes these adaptations of skeletal muscle. 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.


Fatigued muscle produces less force and has a reduced velocity of shortening

Muscle fatigue is defined as the inability to maintain a desired power output—resulting from muscle contraction against a load—with a decline in both force and velocity of shortening. A decline in maximal force production with fatigue results from a reduction in the number of active cross-bridges as well as the force produced per cross-bridge. As fatigue develops, the production of force usually declines earlier and to a greater extent than shortening velocity. Other characteristics of fatigued skeletal muscle are lower rates of both force production and relaxation, owing to impaired release and reuptake of Ca2+ from the sarcoplasmic reticulum (SR). As a result, fast movements become difficult or impossible, and athletic performance suffers accordingly. Nevertheless, fatigue may serve an important protective role in allowing contractions at reduced rates and lower forces while preventing extreme changes in cell composition that could cause damage. Muscle fatigue is reversible with rest, which contrasts with muscle damage or weakness, in which even muscles that are well rested are compromised in their ability to develop force. For example, muscle damage induced by eccentric contractions can easily be mistaken for fatigue, except the recovery period can last for days.

Factors contributing to fatigue include motivation, physical fitness, nutritional status, and the types of motor units (i.e., fibers) recruited with respect to the intensity and duration of activity. As discussed in this major section, fatigue during prolonged activity of moderate intensity involving relatively low frequencies of motor unit activation is caused by different factors than fatigue during bursts of high intensity involving high frequencies of motor unit activation. Moreover, fatigue can result from events occurring in the central nervous system (CNS; central fatigue) as well as from changes within the muscle (peripheral fatigue).

Changes in the CNS produce central fatigue

Central fatigue reflects changes in the CNS and may involve altered input from muscle sensory nerve fibers, reduced excitatory input to motor control centers of the brain and spinal cord, and altered excitability of α and γ motor neurons (see Fig. 15-30). The contributions of these factors vary with the individual and with the nature of activity. For example, central fatigue is likely to play only a minor role in limiting performance of highly trained athletes who have learned to pace themselves according to the task and are mentally conditioned to discomfort and stress. In contrast, central fatigue is likely of greater importance in novice athletes and during repetitive (i.e., boring) tasks. The identification of specific sites involved in central fatigue is difficult because of the complexity of the CNS. Nevertheless, external sensory input, such as shouting and cheering, can often increase muscle force production and physical performance, a finding indicating that pathways proximal to corticospinal outputs can oppose central fatigue.

Impaired excitability and impaired Ca2+ release can produce peripheral fatigue

Transmission block at the neuromuscular junction does not cause muscle fatigue, even though the release of neurotransmitter can decline. Peripheral fatigue reflects a spectrum of events at the level of the muscle fiber, including impairments in the initiation and propagation of muscle action potentials, the release and handling of intracellular Ca2+ for cross-bridge activation, depletion of substrates for energy metabolism, and the accumulation of metabolic byproducts. The nature of fatigue and the time required for recovery vary with the recruitment pattern of motor units and the metabolic properties of their constitutive muscle fibers (Fig. 60-2).

High-Frequency Fatigue With continuous firing of action potentials during intense exercise, Na+ entry and K+ exit exceed the ability of the Na-K pump to restore and maintain normal resting ion concentration gradients. As a result, [K+]o and [Na+]i increase, thus making the resting membrane potential of muscle fibers more positive by 10 to 20 mV. This depolarization inactivates voltage-gated Na+ channels and makes it more difficult to initiate and propagate action potentials. Within the T tubule, such depolarization impairs the ability of L-type Ca2+ channels to activate Ca2+ release channels in the SR (see Fig. 9-3). Fatigue resulting from impaired membrane excitability is particularly apparent at high frequencies of stimulation during recruitment of type II motor units—high-frequency fatigue. On cessation of contractile activity, ionic and ATP homeostasis recovers within 30 minutes; thus, the recovery from high-frequency fatigue occurs relatively quickly.

Low-Frequency Fatigue In prolonged, moderate-intensity exercise, the release of Ca2+ from the SR falls—perhaps reflecting change in either the Ca2+ release channel or its associated proteins—thus leading to a depression in the amplitude of the [Ca2+]i transient that accompanies the muscle twitch. A diminution of Ca2+ release is apparent at all stimulation frequencies. However, the effect on force development is most apparent at low stimulation frequencies, for the following reason. During unfused tetanus (see Fig. 9-11), [Ca2+]i does not continuously remain at high enough levels to saturate troponin C (see Chapter 9). As a result, cross-bridge formation is highly sensitive to the amount of Ca2+ released from the SR with each stimulus. In contrast, with high frequencies of stimulation that produce fused tetanus, [Ca2+]i is at such high levels that Ca2+ continuously saturates troponin C and thereby maximizes cross-bridge interactions and masks the effects of impaired Ca2+ release with each stimulus. Fatigue resulting from impaired Ca2+release is thus particularly apparent at low frequencies of stimulation during recruitment of type I motor units—low-frequency fatigue. Recovery requires several hours.

Fatigue can result from ATP depletion, lactic acid accumulation, and glycogen depletion

ATP Depletion As outlined in Chapter 9, muscle fibers require ATP for contraction, relaxation, and the activity of the membrane pumps that maintain ionic homeostasis. Therefore, the cells must maintain [ATP]i to avoid fatigue (see Chapter 9).

Intense stimulation of muscle fibers (particularly type IIb) requires high rates of ATP utilization, with PCr initially buffering [ATP]i. As fatigue develops, [PCr]i diminishes and [ATP]i can fall from 5 mM to less than 2 mM, particularly at sites of cross-bridge interaction and in the vicinity of membrane pumps, thereby impairing respective ATPase activities. Simultaneously, Pi, ADP, Mg2+, lactate, and H+accumulate in the sarcoplasm. Impairment of the Ca2+ pump at the SR prolongs the Ca2+ transient while reducing the electrochemical driving force for Ca2+ release from the SR. Independently, the fall in [ATP]iand the increase in [Mg2+] can also inhibit Ca2+ release through the ryanodine receptor (see Chapter 9).

Lactic Acid Accumulation Intense activity also activates glycolysis—again, particularly in type IIb fibers—resulting in a high rate of lactic acid production and thus reducing pHi to as low as 6.2 (Equation 60-4). This fall in pHiinhibits myosin ATPase activity and thereby reduces the velocity of shortening. The fall in pHi also inhibits cross-bridge interaction and the binding of Ca2+ to troponin, the Na-K pump, as well as to phosphofructokinase (see Chapter 51), the rate-limiting step of muscle glycolysis. The combined effects of low pHi and high Pi interact to impair the peak force production of muscle fibers more than either agent alone. The mechanisms are reductions in the number of cross-bridges and in the force per cross-bridge by impairing the transition from weak to strong binding states between actin and myosin. In addition, both H+ and Pi reduce Ca2+ sensitivity of contractile proteins, such that higher free [Ca2+]i is required for a given level of force production.

Glycogen Depletion During prolonged exercise of moderate intensity (~50% of maximal aerobic power), and with well maintained O2 delivery, the eventual decrease in glycogen stores in oxidative (type I and IIa) muscle fibers decreases power output. Long-distance runners describe this phenomenon as “hitting the wall.” Muscle glycogen stores are critical because the combination of blood-borne delivery of substrates and the availability of intramuscular fatty acids is inadequate to accommodate the energy requirements. In long-distance running, endurance depends on the absolute amount of glycogen stored in the leg muscles before exercise. To postpone hitting the wall, the athlete must either begin the event with an elevated level of muscle glycogen or race more slowly. Because glycogen storage is primarily a function of diet, carbohydrate loading can increase resting muscle glycogen stores and can postpone the onset of fatigue. Low-carbohydrate diets have the opposite effect. Although physical training has little effect on the capacity for glycolysis, it can promote glycogen storage, particularly if it is combined with a carbohydrate-rich diet. Aerobic training can spare muscle glycogen by adaptations such as mitochondrial proliferation that shift the mix of oxidized fuels toward fatty acids. Indeed, well-trained athletes can maintain moderate-intensity exercise for hours. (See Note: Mechanism of Fatigue during Prolonged Exercise)

During exercise at relatively high intensities (>65% of maximal aerobic power), fatigue develops on the order of tens of minutes. One explanation for this decrement in performance is that type IIb muscle fibers fatigue when their glycogen supplies become exhausted, and the result is a decline in whole-muscle power output.


The O2 required for oxidative metabolism by exercising muscle travels from the atmosphere to the muscle mitochondria in three discrete steps:

1. The uptake of O2 by the lungs depends on pulmonary ventilation.

2. O2 delivery to muscle depends on blood flow and O2 content.

3. The extraction of O2 from blood by muscle depends on O2 delivery and the PO2 gradient between blood and mitochondria.

Maximal O2 uptake by the lungs can exceed resting O2 uptake by more than 20-fold

The respiratory and cardiovascular systems can readily deliver O2 to active skeletal muscle at mild and moderate exercise intensities. As power output increases, the body eventually reaches a point at which the capacity of O2transport systems can no longer keep pace with demand, so the rate of O2 uptake by the lungs (imageO2) plateaus (Fig. 60-6). At rest, imageO2 is typically 250 mL/min for a 70-kg person (see Chapter 29), a value that corresponds to 3.6 mL of O2 consumed per minute for each kg of body mass [mL O2/(min × kg)]. imageO2max is an objective index of the functional capacity of the body’s ability to generate aerobic power. In people who have a deficiency in any part of the O2transport system (e.g., chronic obstructive pulmonary disease or advanced heart disease), imageO2max can be as low as 10 to 20 mL O2/(min × kg). The range for mildly active middle-aged adults is 30 to 40 mL O2/(min × kg); for people in this category, a 3-month program of physical conditioning can increase imageO2max by 20%. In elite endurance athletes, imageO2max may be as high as 80 to 90 mL O2/(min × kg), more than a 20-fold elevation above the resting imageO2. Hemorrhage or high altitude decreases imageO2max, whereas blood transfusion or training increases it.


Figure 60-6 Dependence of imageO2 on mechanical power output. Training increases imageO2max.

The typical method for determining imageO2max is an incremental exercise test on a stationary cycle ergometer or treadmill. Such tests assess training status, predict performance in athletes, and provide an index of functional impairment in patients. During the test, the technician monitors the PO2 and PCO2 of the subject’s expired air, as well as total ventilation. The criteria for achieving imageO2max include (1) an inability to continue the pace at the prescribed power requirement, (2) a leveling off of imageO2 with an increasing power requirement (Fig. 60-6), and (3) a respiratory exchange ratio (imageCO2/imageO2) greater than 1.15. This imageCO2/imageO2 is a transient/non–steady-state occurrence (i.e., not a real respiratory quotient, see Chapter 54) and indicates that a significant hyperventilation, triggered by low blood pH (see Chapter 32), is reducing the body’s CO2 stores.

O2 uptake by muscle is the product of muscle blood flow and O2 extraction

The body’s total store of O2 is ~1 L (mainly in the form of O2 bound to hemoglobin), a volume that (if used completely) could support moderate exercise for 30 seconds at best, heavy exercise for not more than 15 seconds, and maximal exercise for less than 10 seconds. If activity is to persist, the body must continually transport O2 from the ambient air to the muscle mitochondria at a rate that is equivalent to the O2 utilization by the muscle. This increased O2 transport is accomplished by increasing alveolar ventilation to maintain alveolar PO2 levels that are sufficient to saturate arterial blood fully (see Chapter 31) and by increasing cardiac output to ensure a sufficiently high flow of oxygenated blood to the muscles (see Chapter 20). The integrated organ system response to the new, elevated metabolic load involves the close coupling of the pulmonary and the cardiovascular O2 delivery systems to the O2 acceptor mechanisms in the muscle; the response includes sophisticated reflexes to ensure matching of the two processes.

The convective O2 delivery rate is the product of cardiac output (i.e., heart rate × stroke volume) and arterial O2 content:


The rate of O2 uptake by skeletal muscle (imageO2) depends on both the O2 delivery to skeletal muscle and the extraction of O2 by the muscle. According to the Fick equation (see Chapter 17), imageO2 is the product of blood flow to muscle (F) and the arteriovenous (a-v) difference for O2:


The imageO2, established by the rate of oxidative phosphorylation in muscle mitochondria, requires an adequate rate of O2 delivery to the active muscle. Exercise triggers a complicated series of changes in the cardiovascular system that has the net effect of increasing F and redistributing cardiac output away from the splanchnic and renal vascular beds, as well as from inactive to active muscle (see Chapter 25). Increased O2 extraction from the blood by active skeletal muscle occurs at the onset of exercise in response to elevated mitochondrial respiration and the attendant fall in intracellular PO2, which increases the gradient for O2 diffusion from blood to mitochondria.

At the onset of exercise, the content of O2 in the arterial blood (CaO2) actually increases somewhat (e.g., from 20.0 to 20.4 mL O2/mL blood; see Table 29-3) secondary to the increase in alveolar ventilation triggered by the CNS (see Chapter 14). Also as a consequence of the anticipatory hyperventilation, PCO2 actually falls with the onset of exercise. Possible mechanisms of this ventilatory increase include a response to mechanoreceptors in joints and muscles, descending cortical input, or resetting of peripheral chemoreceptors by a reduction in their blood supply (see Chapter 32). The increase in ventilation in anticipation of future needs is enhanced in well-trained athletes.

O2 delivery by the cardiovascular system is the limiting step for maximal O2 utilization

For years, exercise and sports scientists have debated over the factors that limit imageO2max and thus contribute to performance limitations. As noted earlier, the transport of O2 from atmosphere to muscle mitochondria occurs in three steps: uptake, delivery, and extraction. A limitation in any step could be rate limiting for maximal O2 utilization by muscle.

Limited O2 Uptake by Lungs One view is that the lungs limit imageO2max. An inability of alveolar O2 diffusion to saturate arterial blood fully occurs in a subset of elite athletes (including race horses). Thus, a decrease in CaO2 occurs at maximal effort on an incremental test. The inability to saturate arterial blood in athletes could be the consequence of a ventilation-perfusion mismatch at very high cardiac outputs (see Chapter 31). (See Note: Exercise-Induced Arterial Hypoxemia in Females)

Limited O2 Delivery by Cardiovascular System According to the prevalent view, a limitation in O2 transport by the cardiovascular system determines imageO2max. That is, according to the convective flow model, maximal cardiac output, and hence O2 delivery, is the limiting step. Support for this view comes from the observation that training can considerably augment maximal cardiac output and muscle blood flow (see the following section). Moreover, imageO2max largely increases in parallel with these adaptations (Fig. 60-7).


Figure 60-7 Dependence of maximal O2 utilization on O2 delivery. The graph illustrates the relationship between maximal O2 delivery to the peripheral tissues (imageaO2max) and imageO2max for five individuals with different lifestyles. Training increases both O2 delivery and O2 uptake. (Data from Saltin B, Strange S: Med Sci Sports Exerc 1992; 24:30-37.)

Limited O2 Extraction by Muscle A third point of view is that, with increasing demand, extraction by muscle of O2 from blood becomes inadequate despite adequate O2 delivery. According to this diffusive flow model, a major limitation in O2 transport is the kinetics of O2 diffusion from hemoglobin in the red blood cell to the muscle mitochondrial matrix. Thus, anything that lowers either the muscle’s diffusing capacity for O2 or the PO2 gradient between hemoglobin and mitochondria reduces imageO2max.

Effective circulating volume takes priority over cutaneous blood flow for thermoregulation

When we exercise in the heat, our circulatory systems must simultaneously support a large blood flow to both the skin (see Chapter 59) and the contracting muscles, an effort that taxes the cardiac output and effective circulating volume (see Chapter 40). During exercise, the ability to maintain both arterial blood pressure and body core temperature (Tcore) within acceptable physiological limits depends on maintaining an adequate effective circulating volume. Effective circulating volume depends on total blood volume, which, in turn, relies on extracellular fluid volume and on overall vasomotor (primarily venomotor) tone, which is important for distributing blood between central and peripheral pools. Effective circulating volume tends to fall during prolonged exercise, especially exercise in the heat, for three reasons (Fig. 60-8).


Figure 60-8 Effect of exercise on central blood volume. “Valves” refer to the resistance vasculature of respective organs.

First, exercise causes a shift in plasma water from the intravascular to the interstitial space. This transcapillary movement of fluid during exercise primarily reflects increased capillary hydrostatic pressure (see Chapter 20). In addition, increased osmolality within muscle cells removes water from the extracellular space. When exercise intensity exceeds 40% of imageO2max, this loss of plasma water is proportional to the exercise intensity. In extreme conditions, the loss of plasma water can amount to more than 500 mL, or approximately one sixth of the total plasma volume.

Second, exercise causes a loss of total body water through sweating (discussed in the next major section). If exercise is prolonged, without concomitant water intake, sweat loss will cost the body an important fraction of its total water. A loss of body water in excess of 3% of body weight is associated with early signs of heat-related illness, including lightheadedness and disorientation, and it constitutes clinical dehydration.

Third, exercise causes a redistribution of blood volume to the skin because of the increase in cutaneous blood flow in response to body heating (Fig. 60-8). Venous volume in the skin increases as a result of the increased pressure in the compliant vessels as blood flow to the skin rises. No compensatory venoconstriction occurs in the skin because of the overriding action of the temperature control system.

In response to this decrease in effective circulating volume that occurs during exercise, the cardiopulmonary, low-pressure baroreceptors (see Chapter 19) initiate compensatory responses to increase total vascular resistance (Fig. 60-8). This increase in resistance is accomplished through the sympathetic nervous system by (1) increasing the splanchnic vascular resistance, (2) offsetting some of the vasodilatory drive to the skin initiated by the temperature control system, and (3) offsetting some of the vasodilatory drive to the active skeletal muscles.

In conditions of heavy thermal demand, the restriction of peripheral blood flow has the benefit of helping to maintain arterial blood pressure and effective circulating volume, but it carries two liabilities. First, it reduces convective heat transfer from the core to the skin because of the reduced skin blood flow and consequently contributes to excessive heat storage and, in the extreme, heat stroke (see Chapter 59 for the box on this topic). Second, the limitation of blood flow to active muscle may compromise O2 delivery and hence aerobic performance.

In conditions of low thermal and metabolic demand, no serious conflict arises among the systems that regulate effective circulating volume, arterial blood pressure, and body temperature. The cutaneous circulation is capable of handling the heat transfer requirements of the temperature regulatory mechanism without impairing muscle blood flow or cardiac filling pressure.


Eccrine, but not apocrine, sweat glands contribute to temperature regulation

Sweat glands are exocrine glands of the skin, formed by specialized infoldings of the epidermis into the underlying dermis. Sweat glands are of two types: apocrine and eccrine (Fig. 60-9A). The apocrinesweat glands, located in the axillary and anogenital regions of the body, are relatively few in number (~100,000) and large in diameter (2 to 3 mm). Their ducts empty into hair follicles. These glands, which often become active during puberty, produce a turbid and viscous secretion that is rich in lipids and carbohydrates and carries a characteristic body odor that has spawned an entire industry to conceal. Apocrine sweat glands have no role in temperature regulation in humans, although they may act as a source of pheromones.


Figure 60-9 A and B, Sweat glands. The sebaceous gland—the duct of which empties into the hair follicle independently of the duct apocrine sweat gland—secretes sebum, a mixture of fat and the remnants of the cells that secrete the fat.

Eccrine sweat glands are distributed over the majority of the body surface, are numerous (several million), and are small in diameter (50 to 100 μm). The palms of the hands and soles of the feet tend to have both larger and more densely distributed eccrine glands than elsewhere. The full complement of eccrine sweat glands is present at birth and becomes functional within a few months, and the density of these glands decreases as the skin enlarges during normal growth. The essential role of eccrine sweating is temperature regulation, although stimuli such as food, emotion, and pain can evoke secretory activity. Regionally, the trunk, head, and neck show more profuse sweating than the extremities. Sweat production is quantitatively less in women than in men, a finding reflecting less output per gland rather than fewer eccrine sweat glands.

Eccrine sweat glands are tubules comprising a secretory coiled gland and a reabsorptive duct

An eccrine sweat gland is a simple tubular epithelium composed of a coiled gland and a duct (Fig. 60-9B). A rich microvascular network surrounds the entire sweat gland. The coiled gland, located deep in the dermis (see Fig. 15-26), begins at a single blind acinus innervated by postganglionic sympathetic fibers that are cholinergic. The release of acetylcholine stimulates muscarinic receptors on the acinar cells and causes them to secrete into the lumen a clear, odorless solution, similar in composition to protein-free plasma. This primary secretion flows through a long, wavy duct that passes outward through the dermis and epidermis. Along the way, duct cells reabsorb salt and water until the fluid reaches the skin surface through an opening, the sweat pore. Although these pores are too small to be seen with the naked eye, the location of sweat pores is readily identified as sweat droplets form on the skin surface. Both the secretory cells in the coil and the reabsorptive cells in the duct are rich in mitochondria, which are essential for providing sustained energy for the high rates of ion transport necessary for prolonged periods of intense sweating, for example, during exercise in hot environments.

Surrounding the secretory cells in the coil is a layer of myoepithelial cells that resemble smooth muscle and may contract, thereby expressing sweat to the skin surface in a pulsatile fashion. However, this action is not essential because the hydrostatic pressures generated within the gland can exceed 500 mm Hg.

Secretion by Coil Cells The release of acetylcholine onto the secretory coil cells activates muscarinic G protein–coupled receptors (see Chapter 3) and thus leads to the activation of phospholipase C, which, in turn, stimulates protein kinase C and raises [Ca2+]i. These signals somehow trigger the primary secretion, which follows the general mechanism for Cl secretion (see Chapter 5). A Na/K/Cl cotransporter (see Chapter 5) mediates the uptake of Clacross the basolateral membrane, and the Cl exits across the apical membrane through a Cl channel (Fig. 60-9B, lower inset). As Cl diffuses into the lumen, the resulting lumen-negative voltage drives Na+ secretion through the paracellular pathway.

The secretion of NaCl, as well as of urea and lactate, into the lumen sets up an osmotic gradient that drives the secretion of water, so the secreted fluid is nearly isotonic with plasma. This secretion of fluid into the lumen increases hydrostatic pressure at the base of the gland and thereby provides the driving force for moving the fluid along the duct to reach the skin surface.

Reabsorption by Duct Cells As the secreted solution flows along the sweat gland duct, the duct cells reabsorb Na+ and Cl (Fig. 60-9B, upper inset). Na+ enters the duct cells across the apical membrane through epithelial Na+channels (ENaCs), and Cl enters through the cystic fibrosis transmembrane regulator (CFTR). The Na-K pump is responsible for the extrusion of Na+ across the basolateral membrane, and Clexits through a pathway such as a Clchannel. Because the water permeability of the epithelium lining the sweat duct is low, water reabsorption is limited, resulting in a final secretory fluid that is always hypotonic to plasma.

Because sweat is hypotonic, sweating leads to the loss of solute-free water, that is, the loss of more water than salt. As a result, the extracellular fluid contracts and becomes hyperosmolar, thereby causing water to exit from cells. Thus, intracellular fluid volume decreases, and intracellular osmolality increases (see Chapter 5). This water movement helps to correct the fall in extracellular fluid volume. The solute-free water lost in perspiration therefore is ultimately derived from all body fluid compartments.

The NaCl content of sweat increases with the rate of secretion but decreases with acclimatization to heat

Flow Dependence With mild stimulation of acinar cells, the small volume of primary secretion travels slowly along the duct, and the ducts reabsorb nearly all the Na+ and Cl, which can fall to final concentrations as low as ~5 mM (Fig. 60-10). In contrast, with strong cholinergic stimulation, a large volume of primary secretion travels rapidly along the duct, so the load exceeds the capacity of the ductal epithelium to reabsorb Na+ and Cl. Thus, a greater fraction of the secreted Na+ and Cl remains within the lumen, with resulting levels of 50 to 60 mM. In contrast, [K+] in the sweat remains nearly independent of flow at 5 to 10 mM.


Figure 60-10 Flow dependence of sweat composition. Defective Cl (and therefore Na+) reabsorption in cystic fibrosis (CF) patients leads to greater salt loss in sweat.

Cystic Fibrosis In patients with cystic fibrosis (see Chapter 43 for the box on this topic), abnormal sweat gland function is attributable to a defect in the CFTR, a cAMP-regulated Cl channel that is normally present in the apical membrane of sweat gland duct cells. These individuals secrete normal volumes of sweat into the acinus but have a defect in Cl (and, therefore, Na+) absorption as the fluid travels along the duct. As a result, the sweat is relatively rich in NaCl (Fig. 60-10).

Replenishment During a thermoregulatory response in a healthy individual, the rate of sweat production can commonly reach 1 to 2 L/hour, which, after a sufficient time, can represent a substantial fraction of total body water. Such a loss of water and salt requires adequate repletion to preserve fluid and electrolyte balance. Restoring body fluid volume following dehydration is often delayed in humans despite the consumption of fluids. The reason for this delay is that dehydrated persons drink free water, which reduces the osmolality of the extracellular fluid and thus reduces the osmotic drive for drinking (see Chapter 40). This consumed free water distributes into the cells as well as the extracellular space and dilutes the solutes. In addition, the reduced plasma osmolality leads to decreased secretion of arginine vasopressin (i.e., antidiuretic hormone), thus increasing free water excretion by the kidney (see Fig. 40-7).

A more effective means of restoring body fluid volume is to ingest NaCl with water. When Na+ is taken with water (as in many exercise drinks), plasma [Na+] remains elevated throughout a greater duration of the rehydration period and is significantly higher than with the ingestion of water alone. In such conditions, the salt-dependent thirst drive is maintained, and the stimulation of urine production is delayed, thereby leading to more complete restoration of body water content.

Acclimatization With ample, continuing hydration, a heat-acclimatized individual can sweat up to 4 L/hour during maximal sweating. Over several weeks, as the body acclimates to high rates of eccrine sweat production, the ability to reabsorb NaCl increases, and the result is more hypotonic sweat. This adaptation is mediated by aldosterone (see Chapter 35) in response to the net loss of Na+ from the body during the early stages of acclimatization. For example, an individual who is not acclimatized and who sweats profusely can lose more than 30 g of salt per day for the first few days. In contrast, after several weeks of acclimatization, salt loss falls to several grams per day. Thus, an important benefit of physical training and heat acclimatization is the development of more dilute perspiration, which conserves NaCl content and thus effective circulating volume (see Chapter 5) during dehydration.

The hyperthermia of exercise stimulates eccrine sweat glands

As discussed in Chapter 59, the rate of perspiration increases with body Tcore, which, in turn, increases during exercise. The major drive for increased perspiration is the sensing by the hypothalamic centers of increased body Tcore. Physical training increases the sensitivity of the hypothalamic drive to higher Tcore. Indeed, the hyperthermia of exercise causes sweating to begin at a lower skin temperature than does sweating elicited by external heating. The efferent limb of the sweating reflex is mediated by postganglionic sympathetic cholinergic fibers.

Sweating is especially important for thermoregulation under hot ambient conditions and with exercise-induced increases in body temperature. Indeed, as ambient temperature rises to more than 30°C, heat loss through radiation, convection, and conduction (see Chapter 59) becomes progressively ineffective, and evaporative cooling becomes by far the most important mechanism of regulating body temperature. Conversely, evaporative cooling becomes progressively less effective as ambient humidity rises (see Equation 59-5).


Aerobic training requires regular periods of stress and recovery

The body improves its capacity to perform work through physical exertion. However, one must meet four conditions to achieve a training effect, or adaptation to exercise. First, the intensity of the activity must be higher than a critical threshold. For aerobic training (e.g., running, cycling, and swimming), the level of stress increases with the speed of the activity. Second, each period of activity must be of sufficient duration. Third, one must repeat the activity over time on a regular basis (e.g., several times per week). Finally, sufficient rest must occur between each training session because adaptations occur during the recovery period.

A great deal of research has focused on optimizing the foregoing four factors, as well as task specificity for individual athletes competing in specific events. Increasing levels of exertion progressively recruit and thereby adapt type I muscle fibers, followed by type IIa and then type IIb fibers. However, regardless of how long or intensely an individual trains, inactivity reverses these adaptations with an associated decrement in performance. Aerobic conditioning increases imageo2max as well as the body’s ability to eliminate excess heat that is produced during exercise (see Fig. 59-5).

Aerobic training increases maximal O2 delivery by increasing plasma volume and maximal cardiac output

imageO2max could increase as the result of either optimizing O2 delivery to active muscle or optimizing O2 extraction by active muscle, as demonstrated in the following modification of Equation 60-7:


In fact, aerobic training improves both O2 delivery and O2 extraction; the problem for physiologists has been to determine to what extent each system contributes to the whole-body response. For example, an increase in the circulatory system’s capacity to deliver O2 could reflect an increase in either the maximal arterial O2 content or the maximal cardiac output, or both.

Maximizing Arterial O2 Content Several factors could theoretically contribute to maximizing CaO2:

1. Increasing the maximal alveolar ventilation enhances the driving force for O2 uptake by the lungs (see Fig. 31-4).

2. Increasing the capacity for gases to diffuse across the alveolar-capillary barrier in the lungs could enhance O2 uptake at very high cardiac output, particularly at high altitude (see Fig. 27-7).

3. Improving the matching of pulmonary ventilation to perfusion should increase arterial PO2 and the saturation of hemoglobin (see Chapter 31).

4. Increasing the concentration of hemoglobin enables a given volume of arterial blood to carry a greater amount of O2 (see Chapter 29).

In nearly all conditions of exercise, the pulmonary system maintains alveolar PO2 at levels that are sufficiently high to ensure nearly complete (i.e., ~97%) saturation of hemoglobin with O2, even at maximal power output. Thus, it is unlikely that an increase in the maximal alveolar ventilation or pulmonary diffusing capacity could explain the large increase in imageO2max that occurs with training.

CaO2 would be increased by elevating the blood’s hemoglobin concentration. However, no evidence indicates that physical training induces such an increase. On the contrary, [hemoglobin] tends to be slightly lower in endurance athletes, a phenomenon called sports anemia, which reflects an expansion of the plasma compartment (discussed later). Whereas increasing [hemoglobin] provides a greater O2-carrying capacity in blood, maximal O2 transport does not necessarily increase accordingly because blood viscosity and therefore total vascular resistance also increase. The heart would be required to develop higher arterial pressure to generate an equivalent cardiac output. The resultant increased cardiac work would thus be counterproductive to the overall adaptive response. Blood doping—transfusion of blood before competition—is thus not only illegal, but also hazardous to athletes, particularly when water loss through sweating leads to further hemoconcentration.

Maximizing Cardiac Output Factors that contribute to increasing maximal cardiac output include optimizing the increases in heart rate and cardiac stroke volume so their product (i.e., cardiac output) is maximal (Equation 60-9; see Chapter 25). Because training does not increase maximal heart rate and has a relatively small effect on O2 extraction, nearly all the increase in imageO2max that occurs with training must be the result of an increase in maximal cardiac output, the product of optimal heart rate and optimal stroke volume (Equation 60-9). The athlete achieves this increased cardiac output by increasing maximal cardiac stroke volume. Maximal cardiac output can increase by ~40% during physical conditioning that also increases maximal aerobic power by 50%. The difference between 40% and 50% is accounted for by increased extraction: (CaO2 − CvO2)max. This increased extraction is the consequence of capillary proliferation and of increasing the content of mitochondria in muscle fibers that have adapted to endurance training, thereby creating a greater O2 sink under maximal aerobic conditions.

Maximal cardiac stroke volume increases during aerobic training because expansion of the plasma compartment increases the heart’s preload (see Chapter 22), with concomitant hypertrophy of the heart. An increase in preload increases ventricular filling and proportionally increases stroke volume (Starling’s law of the heart), thereby elevating maximal cardiac output accordingly. An additional benefit is that a trained athlete achieves a given cardiac output at a lower heart rate, both at rest and during moderate exercise. Because it is more efficient to increase stroke volume than heart rate, increasing stroke volume reduces the myocardial metabolic load for any particular level of activity.

The expansion of plasma volume probably reflects an increase in albumin content (1 g albumin is dissolved in 18 g of plasma H2O). This increase appears to be caused both by translocation from the interstitial compartment and by increased synthesis by the liver. The result of more colloid in the capillaries is a shift of fluid from the interstitium to the blood. Although the total volume of red blood cells also increases with aerobic training, the plasma volume expansion is greater than the red blood cell expansion, thus reducing the hemoglobin concentration. This sports anemia occurs in highly trained endurance athletes, particularly those acclimatized to hot environments.

The increased blood volume has another beneficial effect. It enhances the ability to maintain high skin blood flow in potentially compromising conditions (e.g., heavy exercise in the heat), thus providing greater heat transport from core to skin and relatively lower storage of heat (see Chapter 59).

Aerobic training enhances O2 diffusion into muscle

Whereas an increase in maximal cardiac output accounts for most of the increased O2 delivery to muscle with training, a lesser fraction reflects increased O2 extraction from blood. Fick’s law describes the diffusion of O2 between the alveolar air and pulmonary capillary blood (see Equation 30-7). A similar relationship describes the diffusion of O2 from the systemic capillary blood to the mitochondria.

The factors that contribute to O2 diffusion are analogous to those that affect the diffusing capacity in the lung. Trained muscle can accommodate a greater maximal blood flow because of the growth of new microvessels, particularly capillaries. Indeed, well-conditioned individuals have a 60% greater number of capillaries per cross-sectional area of muscle than do sedentary people. This increased capillary density increases O2 delivery and thus provides a greater surface area for diffusion. Increase in capillary density also reduces the diffusion distance for O2 between the capillary and muscle fibers (see Fig. 20-4). In addition, training increases total capillary length and volume, prolongs the transit time of red blood cells along capillaries, and thereby promotes the extraction of O2 and nutrients from the blood as well as the removal of metabolic byproducts. Finally, training increases cardiac output and muscle blood flow and preserves a relatively high capillary PO2 throughout the muscle that maintains the driving force for O2 diffusion from capillaries to mitochondria.

Aerobic training increases mitochondrial content

In untrained (but otherwise healthy) individuals, the maximum ability of mitochondria to consume O2 is considerably greater than that of the cardiovascular system to supply O2. Thus, mitochondrial content does not limit imageO2max. We have already seen that endurance training markedly increases O2 delivery. In parallel, endurance training can also increase the mitochondrial content of skeletal muscle fibers nearly 2-fold by stimulating the synthesis of mitochondrial enzymes and other proteins (Fig. 60-11). The stimulus for mitochondrial biogenesis is the repeated activity of the muscle fiber during training, leading to increases in the time-averaged [Ca2+]i, which may act in two ways (Fig. 60-12). One is by directly modulating the transcription of nuclear genes. The other is by increasing cross-bridge cycling and raising [AMP]i, thereby stimulating the fuel sensor AMP kinase—AMPK—which, in turn, can modulate transcription. Some of the newly synthesized proteins are themselves transcription factors that modulate the transcription of nuclear genes. At least one protein (Tfam) enters the mitochondrion and stimulates the transcription and translation of mitochondrial genes for key elements of the electron transport chain. Finally, some newly synthesized proteins encoded by genomic DNA, guided by cytoplasmic chaperones, target the mitochondrial import machinery and become part of multiple subunit complexes—together with proteins of mitochondrial origin.


Figure 60-11 Enzyme adaptation during training. Training causes a slow increase in the level of several enzymes, as well as in the number of capillaries, imageO2max, and size of muscle fibers. These changes reverse rapidly on the cessation of training. (Data from Saltin B, Henriksson J, Nygaard E, Andersen P: Ann N Y Acad Sci 1977; 301:3-29.)


Figure 60-12 Exercise-induced mitochondrial biogenesis. (Data from Chabi B, Adhihetty PJ, Ljubicic V, Hood DA: Med Sci Sports Exerc 2005; 37:2102-2110.)

Because mitochondria create the sink for O2 consumption during the oxidative phosphorylation of ADP to ATP, increased mitochondrial content promotes O2 extraction from the blood. However, the primary benefit from mitochondrial adaptation in aerobic conditioning is the capacity to oxidize substrates, particularly fat, an ability that enhances endurance of muscle. Recall that mitochondria are responsible not only for the citric acid cycle and oxidative phosphorylation but also for β oxidation of fatty acids. In athletes trained for endurance, the greater reliance on fat at a given level of imageO2 is the metabolic basis of glycogen sparing and thus reduced production of lactate and H+.


Books and Reviews

Brooks GA, Fahey TD, Baldwin KM: Exercise Physiology: Human Bioenergetics and Its Applications, 4th ed. Boston: McGraw-Hill; 2004.

Freinkel RK, Woodley DT (eds): The Biology of the Skin. New York: Parthenon, 2001: 47-76.

Hurley HJ: The eccrine sweat gland: Structure and function. In: Freinkel RK, Woodley DT (eds): The Biology of the Skin. New York: Parthenon, 2001: 47-76.

Rowell LR, Shepherd JT (eds): American Physiological Society’s Handbook of Physiology, sect 12: Exercise: Regulation and Integration of Multiple Systems. New York: Oxford University Press; 1995.

Tipton CM (ed): American College of Sports Medicine’s Advanced Exercise Physiology. Baltimore: Lippincott Williams & Wilkins; 2005.

Journal Articles

Burke RE, Levine DN, Tsairis P, Zajac FE: Physiological types and histochemical profiles in motor units of the cat gastrocnemius. J Physiol. 1973; 234:723-748.

Chabi B, Adhihetty PJ, Ljubicic V, Hood DA: How is mitochondrial biogenesis affected in mitochondrial disease? Med Sci Sports Exerc. 2005; 37:2102-2110.

Enoka RM. Morphological features and activation patterns of motor units. J Clin Neurophysiol. 1995; 12:538-559.

Holloszy JO: Biochemical adaptations in muscle: Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J Biol Chem 1967; 242:2278-2282.

Salmons S, Sreter FA: Significance of impulse activity in the transformation of skeletal muscle type. Nature 1976; 263:30-34.

Saltin B, Henriksson J, Nygaard E, Andersen P: Fiber types and metabolic potentials of skeletal muscles in sedentary man and endurance runners. Ann N Y Acad Sci 1977; 301:3-29.

Saltin B, Strange S: Maximal oxygen uptake: Old and new arguments for a cardiovascular limitation. Med Sci Sports Exerc 1992; 24:30-37.

Sato K, Kang WH, Saga K, Sato KT: Biology of sweat glands and their disorders. I. Normal sweat gland function. J Am Acad Dermatol 1989; 20:537-563.

Thomas GD, Segal SS: Neural control of muscle blood flow during exercise. J Appl Physiol 2004; 97:731-738.

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