Skeletal Muscle

Skeletal muscles make up the bulk of muscle in the body and constitute about 40% of total body weight. They position and move the skeleton, as their name suggests. Skeletal muscles are usually attached to bones by tendons made of collagen [here]. The origin of a muscle is the end of the muscle that is attached closest to the trunk or to the more stationary bone. The insertion of the muscle is the more distal {distantia, distant} or more mobile attachment.

When the bones attached to a muscle are connected by a flexible joint, contraction of the muscle moves the skeleton. The muscle is called a flexor if the centers of the connected bones are brought closer together when the muscle contracts, and the movement is called flexion. The muscle is called an extensor if the bones move away from each other when the muscle contracts, and the movement is called extension.

Most joints in the body have both flexor and extensor muscles, because a contracting muscle can pull a bone in one direction but cannot push it back. Flexor-extensor pairs are called antagonistic muscle groups because they exert opposite effects. Figure 12.2 shows a pair of antagonistic muscles in the arm: the biceps brachii {brachion, arm}, which acts as the flexor, and the triceps brachii, which acts as the extensor. When you do a “dumbbell curl” with a weight in your hand, the biceps muscle contracts and the hand and forearm move toward the shoulder. When you lower the weight, the triceps contracts, and the flexed forearm moves away from the shoulder. In each case, when one muscle contracts and shortens, the antagonistic muscle must relax and lengthen.

FIG. 12.2 Antagonistic muscles

Concept Check

  1. Identify as many pairs of antagonistic muscle groups in the body as you can. If you cannot name them, point out the probable location of the flexor and extensor of each group.

Skeletal Muscles Are Composed of Muscle Fibers

Muscles function together as a unit. A skeletal muscle is a collection of muscle cells, or muscle fibers, just as a nerve is a collection of neurons. Each skeletal muscle fiber is a long, cylindrical cell with up to several hundred nuclei near the surface of the fiber (see Anatomy Summary, Fig. 12.3a). Skeletal muscle fibers are the largest cells in the body, created by the fusion of many individual embryonic muscle cells. Committed stem cells called satellite cells lie just outside the muscle fiber membrane. Satellite cells become active and differentiate into muscle when needed for muscle growth and repair.

The fibers in a given muscle are arranged with their long axes in parallel (Fig. 12.3a). Each skeletal muscle fiber is sheathed in connective tissue, with groups of adjacent muscle fibers bundled together into units called fascicles. Collagen, elastic fibers, nerves, and blood vessels are found between the fascicles. The entire muscle is enclosed in a connective tissue sheath that is continuous with the connective tissue around the muscle fibers and fascicles and with the tendons holding the muscle to underlying bones.

Muscle Fiber Anatomy

Muscle physiologists, like neurobiologists, use specialized vocabulary (TBL. 12.1). The cell membrane of a muscle fiber is called the sarcolemma {sarkos, flesh + lemma, shell}, and the cytoplasm is called the sarcoplasm. The main intracellular structures in striated muscles are myofibrils {myo-, muscle}, highly organized bundles of contractile and elastic proteins that carry out the work of contraction.

Table 12.1 Muscle Terminology

General Term Muscle Equivalent
Muscle cell Muscle fiber
Cell membrane Sarcolemma
Cytoplasm Sarcoplasm
Modified endoplasmic reticulum Sarcoplasmic reticulum

Skeletal muscle fibers also contain extensive sarcoplasmic reticulum (SR), a form of modified endoplasmic reticulum that wraps around each myofibril like a piece of lace (Figs. 12.3b, 12.4). The sarcoplasmic reticulum consists of longitudinal tubules with enlarged end regions called the terminal cisternae {cisterna, a reservoir}. The sarcoplasmic reticulum concentrates and sequesters Ca2+ {sequestrare, to put in the hands of a trustee} with the help of a Ca2+ -ATPase in the SR membrane. Calcium release from the SR creates calcium signals that play a key role in contraction in all types of muscle.

FIG. 12.4 T-tubules

The terminal cisternae are adjacent to and closely associated with a branching network of transverse tubules, also known as t-tubules (Fig. 12.4). One t-tubule and its two flanking terminal cisternae are called a triad. The membranes of t-tubules are a continuation of the muscle fiber membrane, which makes the lumen of t-tubules continuous with the extracellular fluid.

To understand how this network of t-tubules deep inside the muscle fiber communicates with the outside, take a lump of soft clay and poke your finger into the middle of it. Notice how the outside surface of the clay (analogous to the surface membrane of the muscle fiber) is now continuous with the sides of the hole that you poked in the clay (the membrane of the t-tubule).

T-tubules allow action potentials to move rapidly from the cell surface into the interior of the fiber so that they reach the terminal cisternae nearly simultaneously. Without t-tubules, the action potential would reach the center of the fiber only by conduction of the action potential through the cytosol, a slower and less direct process that would delay the response time of the muscle fiber.

The cytosol between the myofibrils contains many glycogen granules and mitochondria. Glycogen, the storage form of glucose found in animals, is a reserve source of energy. Mitochondria ontain the enzymes for oxidative phosphorylation of glucose and other biomolecules, so they produce much of the ATP for muscle contraction.

Myofibrils Are Muscle Fiber Contractile Structures

One muscle fiber contains a thousand or more myofibrils that occupy most of the intracellular volume, leaving little space for cytosol and organelles (Fig. 12.3b). Each myofibril is composed of several types of proteins organized into repeating contractile structures called sarcomeres. Myofibril proteins include the motor protein myosin, which forms thick filaments; the microfilament actin [here], which creates thin filaments; the regulatory proteins tropomyosin and troponin; and two giant accessory proteins, titin and nebulin.

Myosin {myo-, muscle} is a motor protein with the ability to create movement [here]. Various isoforms of myosin occur in different types of muscle and help determine the muscle’s speed of contraction. Each myosin molecule is composed of protein chains that intertwine to form a long tail and a pair of tadpole-like heads (Fig. 12.3e). The rod-like tail is stiff, but the protruding myosin heads have an elastic hinge region where the heads join the rods. This hinge region allows the heads to swivel around their point of attachment.

Each myosin head has two protein chains: a heavy chain and a smaller light chain. The heavy chain is the motor domain that binds ATP and uses the energy from ATP’s high-energy phosphate bond to create movement. Because the motor domain acts as an enzyme, it is considered a myosin ATPase. The heavy chain also contains a binding site for actin. In skeletal muscle, about 250 myosin molecules join to create a thick filament. Each thick filament is arranged so that the myosin heads are clustered at each end of the filament, and the central region of the filament is a bundle of myosin tails.

Actin {actum, to do} is a protein that makes up the thin filaments of the muscle fiber. One actin molecule is a globular protein (G-actin), represented in Figure 12.3f by a round ball. Usually, multiple G-actin molecules polymerize to form long chains or filaments, called F-actin. In skeletal muscle, two F-actin polymers twist together like a double strand of beads, creating the thin filaments of the myofibril.

Most of the time, the parallel thick and thin filaments of the myofibril are connected by myosin crossbridges that span the space between the filaments. Each G-actin molecule has a single myosin-binding site, and each myosin head has one actin-binding site and one binding site for ATP. Crossbridges form when the myosin heads of thick filaments bind to actin in the thin filaments (Fig. 12.3d). Crossbridges have two states: low-force (relaxed muscles) and high-force (contracting muscles).

Under a light microscope, the arrangement of thick and thin filaments in a myofibril creates a repeating pattern of alternating light and dark bands (Figs. 12.1a, 12.3c). One repeat of the pattern forms a sarcomere {sarkos, flesh + -mere, a unit or segment}, the contractile unit of the myofibril. Each sarcomere has the following elements (Fig. 12.5):

  1. Z disks. One sarcomere is composed of two Z disks and the filaments found between them. Z disks are zigzag protein structures that serve as the attachment site for thin filaments. The abbreviation Z comes from zwischen, the German word for “between.”

  2. I band. These are the lightest color bands of the sarcomere and represent a region occupied only by thin filaments. The abbreviation I comes from isotropic, a description from early microscopists meaning that this region reflects light uniformly under a polarizing microscope. A Z disk runs through the middle of every I band, so each half of an I band belongs to a different sarcomere.

  3. A band. This is the darkest of the sarcomere’s bands and encompasses the entire length of a thick filament. At the outer edges of the A band, the thick and thin filaments overlap. The center of the A band is occupied by thick filaments only. The abbreviation A comes from anisotropic {an-, not}, meaning that the protein fibers in this region scatter light unevenly.

  4. H zone. This central region of the A band is lighter than the outer edges of the A band because the H zone is occupied by thick filaments only. The H comes from helles, the German word for “clear.”

  5. M line. This band represents proteins that form the attachment site for thick filaments, equivalent to the Z disk for the thin filaments. Each M line divides an A band in half. M is the abbreviation for mittel, the German word for “middle.”

In three-dimensional array, the actin and myosin molecules form a lattice of parallel, overlapping thin and thick filaments, held in place by their attachments to the Z-disk and M-line proteins, respectively (Fig. 12.5b). When viewed end-on, each thin filament is surrounded by three thick filaments, and six thin filaments encircle each thick filament (Fig. 12.5c, rightmost circle).

The proper alignment of filaments within a sarcomere is ensured by two proteins: titin and nebulin (Fig. 12.6). Titin is a huge elastic molecule and the largest known protein, composed of more than 25,000 amino acids. A single titin molecule stretches from one Z disk to the neighboring M line. To get an idea of the immense size of titin, imagine that one titin molecule is an 8-foot-long piece of the very thick rope used to tie ships to a wharf. By comparison, a single actin molecule would be about the length and weight of a single eyelash.

FIG. 12.6 Titin and nebulin

Titin has two functions: (1) it stabilizes the position of the contractile filaments and (2) its elasticity returns stretched muscles to their resting length. Titin is helped by nebulin, an inelastic giant protein that lies alongside thin filaments and attaches to the Z disk. Nebulin helps align the actin filaments of the sarcomere.

Concept Check

  1. Why are the ends of the A band the darkest region of the sarcomere when viewed under the light microscope?

  2. What is the function of t-tubules?

  3. Why are skeletal muscles described as striated?

The Cross Bridge Cycle

Muscle Contraction Creates Force

The contraction of muscle fibers is a remarkable process that enables us to create force to move or to resist a load. In muscle physiology, the force created by contracting muscle is called muscle tension. The load is a weight or force that opposes contraction of a muscle. Contraction, the creation of tension in a muscle, is an active process that requires energy input from ATP. Relaxation is the release of tension created by a contraction.

Figure 12.7 maps the major steps leading up to skeletal muscle contraction.

Events at the Neuromuscular Junction

FIG. 12.7 Summary map of muscle contraction

  1. Events at the neuromuscular junction convert an acetylcholine signal from a somatic motor neuron into an electrical signal in the muscle fiber [here].

  2. Excitation-contraction (E-C) coupling is the process in which muscle action potentials initiate calcium signals that in turn activate a contraction-relaxation cycle.

  3. At the molecular level, a contraction-relaxation cycle can be explained by the sliding filament theory of contraction. In intact muscles, one contraction-relaxation cycle is called a muscle twitch.

In the sections that follow, we start with the sliding filament theory for muscle contraction. From there, we look at the integrated function of a muscle fiber as it undergoes excitation-contraction coupling. The skeletal muscle section ends with a discussion of the innervation of muscles and how muscles move bones around joints.

Concept Check

  1. What are the three anatomical elements of a neuromuscular junction?

  2. What is the chemical signal at a neuromuscular junction?

Actin and Myosin Slide Past Each Other during Contraction

In previous centuries, scientists observed that when muscles move a load, they shorten. This observation led to early theories of contraction, which proposed that muscles were made of molecules that curled up and shortened when active, then relaxed and stretched at rest, like elastic in reverse. The theory received support when myosin was found to be a helical molecule that shortened upon heating (the reason meat shrinks when you cook it).

In 1954, however, scientists Andrew Huxley and Rolf Niedergerke discovered that the length of the A band of a myofibril remains constant during contraction. Because the A band represents the myosin filament, Huxley and Niedergerke realized that shortening of the myosin molecule could not be responsible for contraction. Subsequently, they proposed an alternative model, the sliding filament theory of contraction. In this model, overlapping actin and myosin filaments of fixed length slide past one another in an energy-requiring process, resulting in muscle contraction.

If you examine a myofibril at its resting length, you see that within each sarcomere, the ends of the thick and thin filaments overlap slightly (Fig. 12.5d). In the relaxed state, a sarcomere has a large I band (thin filaments only) and an A band whose length is the length of the thick filament.

When the muscle contracts, the thick and thin filaments slide past each other. The Z disks of the sarcomere move closer together as the sarcomere shortens (Fig. 12.5e). The I band and H zone—regions where actin and myosin do not overlap in resting muscle—almost disappear.

Despite shortening of the sarcomere, the length of the A band remains constant. These changes are consistent with the sliding of thin actin filaments along the thick myosin filaments as the actin filaments move toward the M line in the center of the sarcomere. It is from this process that the sliding filament theory of contraction derives its name.

The sliding filament theory explains how a muscle can contract and create force without creating movement. For example, if you push on a wall, you are creating tension in many muscles of your body without moving the wall. According to the sliding filament theory, tension generated in a muscle fiber is directly proportional to the number of high-force crossbridges between the thick and thin filaments.

Myosin Crossbridges Move Actin Filaments

The movement of myosin crossbridges provides force that pushes the actin filament during contraction. The process can be compared to a competitive sailing team, with many people holding the rope that raises a heavy mainsail. When the order to raise the mainsail comes, each person on the team begins pulling on the rope, hand over hand, grabbing, pulling, and releasing repeatedly as the rope moves past.

In muscle, myosin heads bind to actin molecules, which are the “rope.” A calcium signal initiates the power stroke, when myosin crossbridges swivel and push the actin filaments toward the center of the sarcomere. At the end of a power stroke, each myosin head releases actin, then swivels back and binds to a new actin molecule, ready to start another contractile cycle. During contraction, the heads do not all release at the same time or the fibers would slide back to their starting position, just as the mainsail would fall if the sailors all released the rope at the same time.

The power stroke repeats many times as a muscle fiber contracts. The myosin heads bind, push, and release actin molecules over and over as the thin filaments move toward the center of the sarcomere.

Myosin ATPase

Where does energy for the power stroke come from? The answer is ATP. Myosin converts the chemical bond energy of ATP into the mechanical energy of crossbridge motion.

Myosin is an ATPase (myosin ATPase) that hydrolyzes ATP to ADP and inorganic phosphate (Pi). The energy released by ATP hydrolysis is trapped by myosin and stored as potential energy in the angle between the myosin head and the long axis of the myosin filament. Myosin heads in this position are said to be “cocked,” or ready to rotate. The potential energy of the cocked heads becomes kinetic energy in the power stroke that moves actin.

Calcium Signals Initiate Contraction

How does a calcium signal turn muscle contraction on and off? The answer is found in troponin (TN), a calcium-binding complex of three proteins. Troponin controls the positioning of an elongated protein polymer, tropomyosin {tropos, to turn}.

In resting skeletal muscle, tropomyosin wraps around actin filaments and partially covers actin’s myosin-binding sites (Fig.  12.8a). This is tropomyosin’s blocking or “off” position. Weak, low-force actin-myosin binding can still take place, but myosin is blocked from completing its power stroke, much as the safety latch on a gun keeps the cocked trigger from being pulled. Before contraction can occur, tropomyosin must be shifted to an “on” position that uncovers the remainder of actin’s myosin-binding site.

FIG. 12.8 Troponin and tropomyosin

The off-on positioning of tropomyosin is regulated by troponin. When contraction begins in response to a calcium signal ( in Fig. 12.8b), one protein of the complex—troponin C—binds reversibly to Ca2+ . The calcium-troponin C complex pulls tropomyosin completely away from actin’s myosin-binding sites . This “on” position enables the myosin heads to form strong, high-force crossbridges and carry out their power strokes , moving the actin filament . Contractile cycles repeat as long as the binding sites are uncovered.

For muscle relaxation to occur, Ca2+ concentrations in the cytosol must decrease. By the law of mass action [here], when cytosolic calcium decreases, Ca2+ unbinds from troponin. In the absence of Ca2+, troponin allows tropomyosin to return to the “off” position, covering most of actin’s myosin-binding sites. During the brief portion of the relaxation phase when actin and myosin are not bound to each other, the filaments of the sarcomere slide back to their original positions with the aid of titin and elastic connective tissues within the muscle.

The discovery that Ca2+, not the action potential, is the signal for muscle contraction was the first piece of evidence suggesting that calcium acts as a messenger inside cells. Initially scientists thought that calcium signals occurred only in muscles, but we now know that calcium is an almost universal second messenger [here].

Myosin Heads Step along Actin Filaments

FIG. 12.9 The contraction cycle

Figure 12.9 shows the molecular events of a contractile cycle in skeletal muscle. We will start a cycle with the rigor state {rigere, to be stiff}, where the myosin heads are tightly bound to G-actin molecules. No nucleotide (ATP or ADP) is bound to myosin. In living muscle, the rigor state occurs for only a very brief period. Then:

  1. ATP binds and myosin detaches. An ATP molecule binds to the myosin head. ATP-binding decreases the actin-binding affinity of myosin, and myosin releases from actin.

  2. ATP hydrolysis provides energy for the myosin head to rotate and reattach to actin. The ATP-binding site on the myosin head closes around ATP and hydrolyzes it to ADP and inorganic phosphate (Pi). Both ADP and Pi remain bound to myosin as energy released by ATP hydrolysis rotates the myosin head until it forms a 90° angle with the long axis of the filaments. In this cocked position, myosin binds to a new actin that is 1–3 molecules away from where it started.

    The newly formed actin-myosin crossbridge is weak and low-force because tropomyosin is partially blocking actin’s binding site. However, in this rotated position myosin has stored potential energy, like a stretched spring. The head is cocked, just as someone preparing to fire a gun pulls back or cocks the spring-loaded hammer before firing. Most resting muscle fibers are in this state, cocked and prepared to contract, and just waiting for a calcium signal.

  3. The power stroke. The power stroke (crossbridge tilting) begins after Ca2+ binds to troponin to uncover the rest of the myosin-binding site. The crossbridges transform into strong, high-force bonds as myosin releases Pi. Release of Pi allows the myosin head to swivel. The heads swing toward the M line, sliding the attached actin filament along with them. The power stroke is also called crossbridge tilting because the myosin head and hinge region tilt from a 90° angle to a 45° angle.

  4. Myosin releases ADP. At the end of the power stroke, myosin releases ADP, the second product of ATP hydrolysis. With ADP gone, the myosin head is again tightly bound to actin in the rigor state. The cycle is ready to begin once more as a new ATP binds to myosin.

The Rigor State

The contractile cycle illustrated in Figure 12.9 begins with the rigor state in which no ATP or ADP is bound to myosin. This state in living muscle is normally brief. Living muscle fibers have a sufficient supply of ATP that quickly binds to myosin once ADP is released (step 1). As a result, relaxed muscle fibers remain mostly in step 2.

After death, however, when metabolism stops and ATP supplies are exhausted, muscles are unable to bind more ATP, so they remain in the tightly bound rigor state. In the condition known as rigor mortis, the muscles “freeze” owing to immovable crossbridges. The tight binding of actin and myosin persists for a day or so after death, until enzymes released within the decaying fiber begin to break down the muscle proteins.

Concept Check

  1. Each myosin molecule has binding sites for what molecules?

  2. What is the difference between F-actin and G-actin?

  3. Myosin hydrolyzes ATP to ADP and Pi. Enzymes that hydrolyze ATP are collectively known as                    .

Although the preceding discussion sounds as if we know everything there is to know about the molecular basis of muscle contraction, in reality this is simply our current model. The process is more complex than presented here. It now appears that myosin can influence Ca2+-troponin binding, depending on whether the myosin is bound to actin in a strong (rigor) state, bound to actin in a weak state, or not bound at all. The details of this influence are still being worked out.

Studying contraction and the movement of molecules in a myofibril has proved very difficult. Many research techniques rely on crystallized molecules, electron microscopy, and other tools that cannot be used with living tissues. Often we can see the thick and thin filaments only at the beginning and end of contraction. Progress is being made, however, and perhaps in the next decade you will see a “movie” of muscle contraction, constructed from photographs of sliding filaments.

Concept Check

  1. Name an elastic fiber in the sarcomere that aids relaxation.

  2. In the sliding filament theory of contraction, what prevents the filaments from sliding back to their original position each time a myosin head releases to bind to the next actin binding site?

Acetylcholine Initiates Excitation-Contraction Coupling

Now let’s start at the neuromuscular junction and follow the events leading up to contraction. As you learned earlier in the chapter, this combination of electrical and mechanical events in a muscle fiber is called excitation-contraction coupling. E-C coupling has four major events:

  1. Acetylcholine (ACh) is released from the somatic motor neuron.

  2. ACh initiates an action potential in the muscle fiber.

  3. The muscle action potential triggers calcium release from the sarcoplasmic reticulum.

  4. Calcium combines with troponin and initiates contraction.

Now let’s look at these steps in detail. Acetylcholine released into the synapse at a neuromuscular junction binds to ACh receptor-channels on the motor end plate of the muscle fiber (Fig. 12.10a ) [here]. When the ACh-gated channels open, they allow both Na+ and K+ to cross the membrane. However, Na+ influx exceeds K+ efflux because the electrochemical driving force is greater for Na+ [here]. The addition of net positive charge to the muscle fiber depolarizes the membrane, creating an end-plate potential (EPP). Normally, end-plate potentials always reach threshold and initiate a muscle action potential (Fig. 12.10a ).

The action potential travels across the surface of the muscle fiber and into the t-tubules by the sequential opening of voltage-gated Na+ channels. The process is similar to the conduction of action potentials in axons, although action potentials in skeletal muscle are conducted more slowly than action potentials in myelinated axons [here].

The action potential that moves down the t-tubules causes Ca2+ release from the sarcoplasmic reticulum (Fig. 12.10b , ). Free cytosolic Ca2+ levels in a resting muscle are normally quite low, but after an action potential, they increase about 100-fold. As you’ve learned, when cytosolic Ca2+ levels are high, Ca2+ binds to troponin, tropomyosin moves to the “on” position , and contraction occurs .

At the molecular level, transduction of the electrical signal into a calcium signal requires two key membrane proteins. The t-tubule membrane contains a voltage-sensing L-type calcium channel protein (Cav1.1) called a dihydropyridine (DHP) receptor (Fig. 12.10b ). The DHP receptors, found only in skeletal muscle, are mechanically linked to Ca2+ channels in the adjacent sarcoplasmic reticulum. These SR Ca21 release channels are also known as ryanodine receptors (RyR).

When the depolarization of an action potential reaches a DHP receptor, the receptor changes conformation. The conformation change opens the RyR Ca2+ release channels in the sarcoplasmic reticulum (Fig. 12.10b ). Stored Ca2+ then flows down its electrochemical gradient into the cytosol, where it initiates contraction.

Scientists used to believe that the calcium channel we call the DHP receptor did not form an open channel for calcium entry from the ECF. However, in recent years, it has become apparent that there is a small amount of Ca2+ movement through the DHP receptor, described as excitation-coupled Ca2+ entry. However, skeletal muscle contraction will still take place if there is no ECF Ca2+ to come through the channel, so the physiological role of excitation-coupled Ca2+ entry is unclear.

Relaxation

To end a contraction, calcium must be removed from the cytosol. The sarcoplasmic reticulum pumps Ca2+ back into its lumen using a Ca21-ATPase [here]. As the free cytosolic Ca2+ concentration decreases, the equilibrium between bound and unbound Ca2+ is disturbed and calcium releases from troponin. Removal of Ca2+ allows tropomyosin to slide back and block actin’s myosin-binding site. As the crossbridges release, the muscle fiber relaxes with the help of elastic fibers in the sarcomere and in the connective tissue of the muscle.

Timing of E-C Coupling

The graphs in Figure 12.11 show the timing of electrical and mechanical events during E-C coupling. The somatic motor neuron action potential is followed by the skeletal muscle action potential, which in turn is followed by contraction. A single contraction-relaxation cycle in a skeletal muscle fiber is known as a twitch. Notice that there is a short delay—the latent period—between the muscle action potential and the beginning of muscle tension development. This delay represents the time required for calcium release and binding to troponin.

FIG. 12.11 Timing of E-C coupling

Figure Questions: Movement of what ion(s) in what direction(s) creates

  1. (a) the neuronal action potential?

  2. (b) the muscle action potential?

Once contraction begins, muscle tension increases steadily to a maximum value as crossbridge interaction increases. Tension then decreases in the relaxation phase of the twitch. During relaxation, elastic elements of the muscle return the sarcomeres to their resting length.

A single action potential in a muscle fiber evokes a single twitch (Fig. 12.11, bottom graph). However, muscle twitches vary from fiber to fiber in the speed with which they develop tension (the rising slope of the twitch curve), the maximum tension they achieve (the height of the twitch curve), and the duration of the twitch (the width of the twitch curve). You will learn about factors that affect these parameters in upcoming sections. First, we discuss how muscles produce ATP to provide energy for contraction and relaxation.

Concept Check

  1. Which part of contraction requires ATP? Does relaxation require ATP?

  2. What events are taking place during the latent period before contraction begins?

Skeletal Muscle Contraction Requires a Steady Supply of ATP

The muscle fiber’s use of ATP is a key feature of muscle physiology. Muscles require energy constantly: during contraction for crossbridge movement and release, during relaxation to pump Ca2+ back into the sarcoplasmic reticulum, and after E-C coupling to restore Na+ and K+ to the extracellular and intracellular compartments, respectively. Where do muscles get the ATP they need for this work?

The amount, or pool, of ATP stored in a muscle fiber at any one time is sufficient for only about eight twitches. As ATP is converted to ADP and Pi during contraction, the ATP pool must be replenished by transfer of energy from other high-energy phosphate bonds or by synthesis of ATP through the slower metabolic pathways of glycolysis and oxidative phosphorylation.

The backup energy source of muscles is phosphocreatine, a molecule whose high-energy phosphate bonds are created from creatine and ATP when muscles are at rest (Fig. 12.12). When muscles become active, such as during exercise, the high-energy phosphate group of phosphocreatine is quickly transferred to ADP, creating more ATP to power the muscles.

FIG. 12.12 Phosphocreatine

The enzyme that transfers the phosphate group from phosphocreatine to ADP is creatine kinase (CK), also known as creatine phosphokinase (CPK). Muscle cells contain large amounts of this enzyme. Consequently, elevated blood levels of creatine kinase usually indicate damage to skeletal or cardiac muscle. Because the two muscle types contain different isozymes [here], clinicians can distinguish cardiac tissue damage during a heart attack from skeletal muscle damage.

Energy stored in high-energy phosphate bonds is very limited, so muscle fibers must use metabolism of biomolecules to transfer energy from covalent bonds to ATP. Carbohydrates, particularly glucose, are the most rapid and efficient source of energy for ATP production. Glucose is metabolized through glycolysis to pyruvate [here]. In the presence of adequate oxygen, pyruvate goes into the citric acid cycle, producing about 30 ATP for each molecule of glucose.

When oxygen concentrations fall during strenuous exercise, muscle fiber metabolism relies more on anaerobic glycolysis. In this pathway, glucose is metabolized to lactate with a yield of only 2 ATP per glucose [here]. Anaerobic metabolism of glucose is a quicker source of ATP but produces many fewer ATP per glucose. When energy demands are greater than the amount of ATP that can be produced through anaerobic glucose metabolism, muscles can function for only a short time without fatiguing.

Muscle fibers also obtain energy from fatty acids, although this process always requires oxygen. During rest and light exercise, skeletal muscles burn fatty acids along with glucose, one reason that modest exercise programs of brisk walking are an effective way to reduce body fat. However, the metabolic process by which fatty acids are converted to acetyl CoA is relatively slow and cannot produce ATP rapidly enough to meet the energy needs of muscle fibers during strenuous exercise. Under these conditions, muscle fibers rely more on glucose.

Proteins normally are not a source of energy for muscle contraction. Most amino acids found in muscle fibers are used to synthesize proteins rather than to produce ATP.

Do muscles ever run out of ATP? You might think so if you have ever exercised to the point of fatigue, the point at which you feel that you cannot continue or your limbs refuse to obey commands from your brain. Most studies show, however, that even intense exercise uses only 30% of the ATP in a muscle fiber. The condition we call fatigue must come from other changes in the exercising muscle.

Concept Check

  1. According to the convention for naming enzymes, what does the name creatine kinase tell you about this enzyme’s function? [Hint: here]

  2. The reactions in Figure 12.12 show that creatine kinase catalyzes the creatine-phosphocreatine reaction in both directions. What then determines the direction that the reaction goes at any given moment? [Hint: here]

Fatigue Has Multiple Causes

The physiological term fatigue describes a reversible condition in which an exercising muscle is no longer able to generate or sustain the expected power output. Fatigue is highly variable. It is influenced by the intensity and duration of the contractile activity, by whether the muscle fiber is using aerobic or anaerobic metabolism, by the composition of the muscle, and by the fitness level of the individual. The study of fatigue is complex, and research in this area is complicated by the fact that experiments are done under a wide range of conditions, from “skinned” (sarcolemma removed) single muscle fibers to exercising humans. Although many different factors have been associated with fatigue, the factors that cause fatigue are still uncertain.

Factors that have been proposed to play a role in fatigue are classified into central fatigue mechanisms, which arise in the central nervous system, and peripheral fatigue mechanisms, which arise anywhere between the neuromuscular junction and the contractile elements of the muscle (Fig. 12.13). Most experimental evidence suggests that muscle fatigue arises from excitation-contraction failure in the muscle fiber rather than from failure of control neurons or neuromuscular transmission.

FIG. 12.13 Muscle fatigue

Central fatigue includes subjective feelings of tiredness and a desire to cease activity. Several studies have shown that this psychological fatigue precedes physiological fatigue in the muscles and therefore may be a protective mechanism. Low pH from acid production during ATP hydrolysis is often mentioned as a possible cause of fatigue, and some evidence suggests that acidosis may influence the sensation of fatigue perceived by the brain. However, homeostatic mechanisms for pH balance maintain blood pH at normal levels until exertion is nearly maximal, so pH as a factor in central fatigue probably applies only in cases of maximal exertion.

Neural causes of fatigue could arise either from communication failure at the neuromuscular junction or from failure of the CNS command neurons. For example, if ACh is not synthesized in the axon terminal fast enough to keep up with neuron firing rate, neurotransmitter release at the synapse decreases. Consequently, the muscle end-plate potential fails to reach the threshold value needed to trigger a muscle fiber action potential, resulting in contraction failure. This type of fatigue is associated with some neuromuscular diseases, but it is probably not a factor in normal exercise.

Fatigue within the muscle fiber (peripheral fatigue) could occur in any of several sites. In extended submaximal exertion, fatigue is associated with the depletion of muscle glycogen stores. Because most studies show that lack of ATP is not a limiting factor, glycogen depletion may be affecting some other aspect of contraction, such as the release of Ca2+ from the sarcoplasmic reticulum.

The cause of fatigue in short-duration maximal exertion seems to be different. One theory is based on the increased levels of inorganic phosphate (Pi) produced when ATP and phosphocreatine are used for energy in the muscle fiber. Elevated cytoplasmic Pi may slow Pi release from myosin and thereby alter the power stroke (see Fig. 12.9).

Another theory suggests that elevated phosphate levels decrease Ca2+ release because the phosphate combines with Ca2+ to become calcium phosphate. Some investigators feel that alterations in Ca2+ release from the sarcoplasmic reticulum play a major role in fatigue.

Ion imbalances have also been implicated in fatigue. During maximal exercise, K+ leaves the muscle fiber with each action potential, and as a result K+ concentrations rise in the extracellular fluid of the t-tubules. The shift in K+ alters the membrane potential of the muscle fiber. Changes in Na+-K+-ATPase activity may also be involved. In short, muscle fatigue is a complex phenomenon with multiple causes that interact with each other.

Concept Check

  1. If K+ concentration increases in the extracellular fluid surrounding a cell but does not change significantly in the cell’s cytoplasm, the cell membrane (depolarizes/hyperpolarizes) and becomes (more/less) negative.

Skeletal Muscle Is Classified by Speed and Fatigue Resistance

Skeletal muscle fibers have traditionally been classified on the basis of their speed of contraction and their resistance to fatigue with repeated stimulation. But like so much in physiology, the more scientists learn, the more complicated the picture becomes. The current classification of muscle fiber types depends on the isoform of myosin expressed in the fiber (type 1 or type 2).

Muscle fiber types are not fixed for life. Muscles have plasticity and can shift their type depending on their activity. The currently accepted muscle fiber types in humans include slow-twitch fibers (also called ST or type 1), fast-twitch oxidative-glycolytic fibers (FOG or type 2A), and fast-twitch glycolytic fibers (FG or type 2X). Type 2X was previously identified as type 2B, which is found in other animals but not in humans.

Fast-twitch muscle fibers (type 2) develop tension two to three times faster than slow-twitch fibers (type 1). The speed with which a muscle fiber contracts is determined by the isoform of myosin ATPase present in the fiber’s thick filaments. Fast-twitch fibers split ATP more rapidly and can, therefore, complete multiple contractile cycles more rapidly than slow-twitch fibers. This speed translates into faster tension development in the fast-twitch fibers.

The duration of contraction also varies according to fiber type. Twitch duration is determined largely by how fast the sarcoplasmic reticulum removes Ca2+ from the cytosol. As cytosolic Ca2+ concentrations fall, Ca2+ unbinds from troponin, allowing tropomyosin to move into position to partially block the myosin-binding sites. With the power stroke inhibited in this way, the muscle fiber relaxes.

Fast-twitch fibers pump Ca2+ into their sarcoplasmic reticulum more rapidly than slow-twitch fibers do, so fast-twitch fibers have quicker twitches. The twitches in fast-twitch fibers last only about 7.5 msec, making these muscles useful for fine, quick movements, such as playing the piano. Contractions in slow-twitch muscle fibers may last more than 10 times as long. Fast-twitch fibers are used occasionally, but slow-twitch fibers are used almost constantly for maintaining posture, standing, or walking.

The second major difference between muscle fiber types is their ability to resist fatigue. Glycolytic fibers (fast-twitch type 2X) rely primarily on anaerobic glycolysis to produce ATP. However, the accumulation of H+ from ATP hydrolysis contributes to acidosis, a condition implicated in the development of fatigue, as noted previously. As a result, glycolytic fibers fatigue more easily than do oxidative fibers, which do not depend on anaerobic metabolism.

Oxidative fibers rely primarily on oxidative phosphorylation [here] for production of ATP—hence their descriptive name. These fibers, which include type 1 slow-twitch fibers and type 2A fast-twitch oxidative-glycolytic fibers, have more mitochondria (the site of enzymes for the citric acid cycle and oxidative phosphorylation) than glycolytic fibers do. They also have more blood vessels in their connective tissue to bring oxygen to the cells (Fig. 12.14).

FIG. 12.14 Fast-twitch and slow-twitch muscles

The efficiency with which muscle fibers obtain oxygen is a factor in their preferred method of glucose metabolism. Oxygen in the blood must diffuse into the interior of muscle fibers in order to reach the mitochondria. This process is facilitated by the presence of myoglobin, a red oxygen-binding pigment with a high affinity for oxygen. This affinity allows myoglobin to act as a transfer molecule, bringing oxygen more rapidly to the interior of the fibers. Because oxidative fibers contain more myoglobin, oxygen diffusion is faster than in glycolytic fibers. Oxidative fibers are described as red muscle because large amounts of myoglobin give them their characteristic color.

In addition to myoglobin, oxidative fibers have smaller diameters, so the distance through which oxygen must diffuse before reaching the mitochondria is shorter. Because oxidative fibers have more myoglobin and more capillaries to bring blood to the cells and are smaller in diameter, they maintain a better supply of oxygen and are able to use oxidative phosphorylation for ATP production.

2X glycolytic fibers, in contrast, are described as white muscle because of their lower myoglobin content. These muscle fibers are also larger in diameter than type 1 slow-twitch fibers. The combination of larger size, less myoglobin, and fewer blood vessels means that glycolytic fibers are more likely to run out of oxygen after repeated contractions. Glycolytic fibers therefore rely primarily on anaerobic glycolysis for ATP synthesis and fatigue most rapidly.

Type 2A fast-twitch oxidative-glycolytic fibers exhibit properties of both oxidative and glycolytic fibers. They are smaller than fast-twitch glycolytic fibers and use a combination of oxidative and glycolytic metabolism to produce ATP. Because of their intermediate size and the use of oxidative phosphorylation for ATP synthesis, type 2A fibers are more fatigue resistant than their 2X fast-twitch glycolytic cousins. Type 2A fibers, like type 1 slow-twitch fibers, are classified as red muscle because of their myoglobin content.

Human muscles are a mixture of fiber types, with the ratio of types varying from muscle to muscle and from one individual to another. For example, who would have more fast-twitch fibers in leg muscles, a marathon runner or a high-jumper? Characteristics of the three muscle fiber types are compared in Table 12.2.

Table 12.2 Characteristics of Muscle Fiber Types

Slow-Twitch Oxidative; Red Muscle (Type 1) Fast-Twitch Oxidative-Glycolytic; Red Muscle (Type 2A) Fast-Twitch Glycolytic; White Muscle (Type 2X)
Speed of Development of Maximum Tension Slowest Intermediate Fastest
Myosin ATPase Activity Slow Fast Fast
Diameter Small Medium Large
Contraction Duration Longest Short Short
Ca2+-ATPase Activity in SR Moderate High High
Endurance Fatigue resistant Fatigue resistant Easily fatigued
Use Most used: posture Standing, walking Least used: jumping; quick, fine movements
Metabolism Oxidative; aerobic Glycolytic but becomes more oxidative with endurance training Glycolytic; more anaerobic than fast-twitch oxidative-glycolytic type
Capillary Densitys High Medium Low
Mitochondria Numerous Moderate Few
Color Dark red (myoglobin) Red Pale

Resting Fiber Length Affects Tension

In a muscle fiber, the tension developed during a twitch is a direct reflection of the length of individual sarcomeres before contraction begins (Fig. 12.15). Each sarcomere contracts with optimum force if it is at optimum length (neither too long nor too short) before the contraction begins. Fortunately, the normal resting length of skeletal muscles usually ensures that sarcomeres are at optimum length when they begin a contraction.

FIG. 12.15 Length-tension relationships

At the molecular level, sarcomere length reflects the overlap between the thick and thin filaments (Fig. 12.15). The sliding filament theory predicts that the tension generated by a muscle fiber is directly proportional to the number of crossbridges formed between the thick and thin filaments. If the fibers start a contraction at a very long sarcomere length, the thick and thin filaments barely overlap and form few crossbridges (Fig. 12.15e). This means that in the initial part of the contraction, the sliding filaments interact only minimally and therefore cannot generate much force.

At the optimum sarcomere length (Fig. 12.15c), the filaments begin contracting with numerous crossbridges between the thick and thin filaments, allowing the fiber to generate optimum force in that twitch. If the sarcomere is shorter than optimum length at the beginning of the contraction (Fig. 12.15b), the thick and thin fibers have too much overlap before the contraction begins. Consequently, the thick filaments can move the thin filaments only a short distance before the thin actin filaments from opposite ends of the sarcomere start to overlap. This overlap prevents crossbridge formation.

If the sarcomere is so short that the thick filaments run into the Z disks (Fig. 12.15a), myosin is unable to find new binding sites for crossbridge formation, and tension decreases rapidly. Thus, the development of single-twitch tension in a muscle fiber is a passive property that depends on filament overlap and sarcomere length.

Force of Contraction Increases with Summation

Although we have just seen that single-twitch tension is determined by the length of the sarcomere, it is important to note that a single twitch does not represent the maximum force that a muscle fiber can develop. The force generated by the contraction of a single muscle fiber can be increased by increasing the rate (frequency) at which muscle action potentials stimulate the muscle fiber.

A typical muscle action potential lasts between 1 and 3 msec, while the muscle contraction may last 100 msec (see Fig. 12.11). If repeated action potentials are separated by long intervals of time, the muscle fiber has time to relax completely between stimuli (Fig. 12.16a). If the interval of time between action potentials is shortened, the muscle fiber does not have time to relax completely between two stimuli, resulting in a more forceful contraction (Fig. 12.16b). This process is known as summation and is similar to the temporal summation of graded potentials that takes place in neurons [here].

FIG. 12.16 Summation of contractions

If action potentials continue to stimulate the muscle fiber repeatedly at short intervals (high frequency), relaxation between contractions diminishes until the muscle fiber achieves a state of maximal contraction known as tetanus. There are two types of tetanus. In incomplete, or unfused, tetanus, the stimulation rate of the muscle fiber is not at a maximum value, and consequently the fiber relaxes slightly between stimuli (Fig. 12.16c). In complete, or fused, tetanus, the stimulation rate is fast enough that the muscle fiber does not have time to relax. Instead, it reaches maximum tension and remains there (Fig. 12.16d).

Thus, it is possible to increase the tension developed in a single muscle fiber by changing the rate at which action potentials occur in the fiber. Muscle action potentials are initiated by the somatic motor neuron that controls the muscle fiber.

Concept Check

  1. Summation in muscle fibers means that the        of the fiber increases with repeated action potentials.

  2. Temporal summation in neurons means that the         of the neuron increases when two depolarizing stimuli occur close together in time.

A Motor Unit Is One Motor Neuron and Its Muscle Fibers

The basic unit of contraction in an intact skeletal muscle is a motor unit, composed of a group of muscle fibers that function together and the somatic motor neuron that controls them (Fig.  12.17). When the somatic motor neuron fires an action potential, all muscle fibers in the motor unit contract. Note that although one somatic motor neuron innervates multiple fibers, each muscle fiber is innervated by only a single neuron.

FIG. 12.17 Motor units

The number of muscle fibers in a motor unit varies. In muscles used for fine motor actions, such as the extraocular muscles that move the eyes or the muscles of the hand, one motor unit contains as few as three to five muscle fibers. If one such motor unit is activated, only a few fibers contract, and the muscle response is quite small. If additional motor units are activated, the response increases by small increments because only a few more muscle fibers contract with the addition of each motor unit. This arrangement allows fine gradations of movement.

In muscles used for gross motor actions such as standing or walking, each motor unit may contain hundreds or even thousands of muscle fibers. The gastrocnemius muscle in the calf of the leg, for example, has about 2000 muscle fibers in each motor unit. Each time an additional motor unit is activated in these muscles, many more muscle fibers contract, and the muscle response jumps by correspondingly greater increments.

All muscle fibers in a single motor unit are of the same fiber type. For this reason there are fast-twitch motor units and slow-twitch motor units. Which kind of muscle fiber associates with a particular neuron appears to be a function of the neuron. During embryological development, each somatic motor neuron secretes a growth factor that directs the differentiation of all muscle fibers in its motor unit so that they develop into the same fiber type.

Intuitively, it would seem that people who inherit a predominance of one fiber type over another would excel in certain sports. They do, to some extent. Endurance athletes, such as distance runners and cross-country skiers, have a predominance of slow-twitch fibers, whereas sprinters, ice hockey players, and weight lifters tend to have larger percentages of fast-twitch fibers.

Inheritance is not the only determining factor for fiber composition in the body, however, because the metabolic characteristics of muscle fibers have some plasticity. With endurance training, the aerobic capacity of some fast-twitch fibers can be enhanced until they are almost as fatigue-resistant as slow-twitch fibers. Because the conversion occurs only in those muscles that are being trained, a neuromodulator chemical is probably involved. In addition, endurance training increases the number of capillaries and mitochondria in the muscle tissue, allowing more oxygen-carrying blood to reach the contracting muscle and contributing to the increased aerobic capacity of the muscle fibers.

Contraction Force Depends on the Types and Numbers of Motor Units

Within a skeletal muscle, each motor unit contracts in an all-or-none manner. How then can muscles create graded contractions of varying force and duration? The answer lies in the fact that muscles are composed of multiple motor units of different types (Fig. 12.17). This diversity allows the muscle to vary contraction by (1) changing the types of motor units that are active or (2) changing the number of motor units that are responding at any one time.

The force of contraction in a skeletal muscle can be increased by recruiting additional motor units. Recruitment is controlled by the nervous system and proceeds in a standardized sequence. A weak stimulus directed onto a pool of somatic motor neurons in the central nervous system activates only the neurons with the lowest thresholds [here]. Studies have shown that these low-threshold neurons control fatigue-resistant slow-twitch fibers, which generate minimal force.

As the stimulus onto the motor neuron pool increases in strength, additional motor neurons with higher thresholds begin to fire. These neurons in turn stimulate motor units composed of fatigue-resistant fast-twitch oxidative-glycolytic fibers. Because more motor units (and, thus, more muscle fibers) are participating in the contraction, greater force is generated in the muscle.

As the stimulus increases to even higher levels, somatic motor neurons with the highest thresholds begin to fire. These neurons stimulate motor units composed of glycolytic fast-twitch fibers. At this point, the muscle contraction is approaching its maximum force. Because of differences in myosin and crossbridge formation, fast-twitch fibers generate more force than slow-twitch fibers do. However, because fast-twitch fibers fatigue more rapidly, it is impossible to hold a muscle contraction at maximum force for an extended period of time. You can demonstrate this by clenching your fist as hard as you can: How long can you hold it before some of the muscle fibers begin to fatigue?

Sustained contractions in a muscle require a continuous train of action potentials from the central nervous system to the muscle. As you learned earlier, however, increasing the stimulation rate of a muscle fiber results in summation of its contractions. If the muscle fiber is easily fatigued, summation leads to fatigue and diminished tension (Fig. 12.16d).

One way the nervous system avoids fatigue in sustained contractions is by asynchronous recruitment of motor units. The nervous system modulates the firing rates of the motor neurons so that different motor units take turns maintaining muscle tension. The alternation of active motor units allows some of the motor units to rest between contractions, preventing fatigue.

Asynchronous recruitment prevents fatigue only in submaximal contractions, however. In high-tension, sustained contractions, the individual motor units may reach a state of unfused tetanus, in which the muscle fibers cycle between contraction and partial relaxation. In general, we do not notice this cycling because the different motor units in the muscle are contracting and relaxing at slightly different times. As a result, the contractions and relaxations of the motor units average out and appear to be one smooth contraction. But as different motor units fatigue, we are unable to maintain the same amount of tension in the muscle, and the force of the contraction gradually decreases.

Concept Check

  1. Which type of runner would you expect to have more slow-twitch fibers, a sprinter or a marathoner?

  2. What is the response of a muscle fiber to an increase in the firing rate of the somatic motor neuron?

  3. How does the nervous system increase the force of contraction in a muscle composed of many motor units?