A single muscle fiber may contain 15 billion thick filaments. When that muscle fiber is actively contracting, each thick filament breaks down roughly 2500 ATP molecules per second. Because even a small skeletal muscle contains thousands of muscle fibers, the ATP demands of a contracting skeletal muscle are enormous. In practical terms, the demand for ATP in a contracting muscle fiber is so high that it would be impossible to have all the necessary energy available as ATP before the contraction begins. Instead, a resting muscle fiber contains only enough ATP and other high-energy compounds to sustain a contraction until additional ATP can be generated. Throughout the rest of the contraction, the muscle fiber will generate ATP at roughly the same rate as it is used.

ATP and CP Reserves

The primary function of ATP is the transfer of energy from one location to another rather than the long-term storage of energy. At rest, a skeletal muscle fiber produces more ATP than it needs. Under these conditions, ATP transfers energy to creatine. Creatine is a small molecule that muscle cells assemble from fragments of amino acids. The energy transfer creates another high-energy compound, creatine phosphate (CP), or phosphorylcreatine:

During a contraction, each myosin cross-bridge breaks down ATP, producing ADP and a phosphate group. The energy stored in creatine phosphate is then used to "recharge" ADP, converting it back to ATP through the reverse reaction:

The enzyme that facilitates this reaction is creatine phosphokinase (CPK or CK). When muscle cells are damaged, CPK leaks across the cell membranes and into the bloodstream. Thus, a high blood concentration of CPK usually indicates serious muscle damage.

The energy reserves of a representative muscle fiber are indicated in Table 10-2. A resting skeletal muscle fiber contains about six times as much creatine phosphate as ATP. But when a muscle fiber is undergoing a sustained contraction, these energy reserves are exhausted in only about 15 seconds. The muscle fiber must then rely on other mechanisms to convert ADP to ATP.

ATP Generation

We learned in Chapter 3 that most cells in the body generate ATP through aerobic metabolism in mitochondria and through glycolysis in the cytoplasm.

Aerobic Metabolism Aerobic metabolism normally provides 95 percent of the ATP demands of a resting cell. In this process, mitochondria absorb oxygen, ADP, phosphate ions, and organic substrates from the surrounding cytoplasm. The substrates then enter the TCA (tricarboxylic acid) cycle (also known as the citric acid cycle or the Krebs cycle), an enzymatic pathway that breaks down organic molecules. The carbon atoms are released as carbon dioxide. The hydrogen atoms are shuttled to respiratory enzymes in the inner mitochondrial membrane, where their electrons are removed. After a series of intermediate steps, the protons and electrons are combined with oxygen to form water. Along the way, large amounts of energy are released and used to make ATP. The entire process is very efficient; for each organic molecule "fed" to the TCA cycle, the cell will gain 17 ATP molecules.

Resting skeletal muscle fibers rely almost exclusively on the aerobic metabolism of fatty acids to generate ATP. When the muscle starts contracting, the mitochondria begin breaking down molecules of pyruvic acid instead of fatty acids. The pyruvic acid is provided by the enzymatic pathway of glycolysis.

Glycolysis Glycolysis is the breakdown of glucose to pyruvic acid in the cytoplasm of a cell. It is called an anaerobic process, because it does not require oxygen. Glycolysis provides a net gain of 2 ATP and generates 2 pyruvic acid molecules from each glucose molecule. The ATP produced by glycolysis is thus only a small fraction of that produced by aerobic metabolism, in which the breakdown of the 2 pyruvic acid molecules in mitochondria would generate 34 ATP. Yet, because it can proceed in the absence of oxygen, glycolysis can be important when the availability of oxygen limits the rate of mitochondrial ATP production.

In most skeletal muscles, glycolysis is the primary source of ATP during peak periods of activity. The glucose broken down under these conditions is obtained primarily from the reserves of glycogen in the sarcoplasm. Glycogen, diagrammed in Figure 2-11 is a polysaccharide chain of glucose molecules. Typical skeletal muscle fibers contain large glycogen reserves, which may account for 1.5 percent of the total muscle weight. When the muscle fiber begins to run short of ATP and CP, enzymes split the glycogen molecules apart, releasing glucose, which can be used to generate more ATP. As the level of muscular activity increases and these reserves are mobilized, the pattern of energy production and use changes.

Energy Use and the Level of Muscle Activity

In a resting skeletal muscle (Figure 10-18a), the demand for ATP is low. More than enough oxygen is available for the mitochondria to meet that demand, and they produce a surplus of ATP. The extra ATP is used to build up reserves of CP and glycogen. Resting muscle fibers absorb fatty acids and glucose that are delivered by the bloodstream. The fatty acids are broken down in the mitochondria, and the ATP generated is used to convert creatine to creatine phosphate and glucose to glycogen.

At moderate levels of activity (Figure 10-18b), the demand for ATP increases. This demand is met by the mitochondria. As the rate of mitochondrial ATP production rises, so does the rate of oxygen consumption. Oxygen availability is not a limiting factor, because oxygen can diffuse into the muscle fiber fast enough to meet mitochondrial needs. But all the ATP produced is needed by the muscle fiber, and no surplus is available. The skeletal muscle now relies primarily on the aerobic metabolism of pyruvic acid to generate ATP. The pyruvic acid is provided by glycolysis, which breaks down glucose molecules obtained from glycogen in the muscle fiber. If glycogen reserves are low, the muscle fiber can also break down other substrates, such as lipids or amino acids. As long as the demand for ATP can be met by mitochondrial activity, the ATP provided by glycolysis makes a relatively minor contribution to the total energy budget of the muscle fiber.

At peak levels of activity, the ATP demands are enormous and mitochondrial ATP production rises to a maximum. This maximum rate is determined by the availability of oxygen, and oxygen cannot diffuse into the muscle fiber fast enough to enable the mitochondria to produce the required ATP. At peak levels of exertion, mitochondrial activity can provide only about one-third of the ATP needed. The remainder is produced through glycolysis (Figure 10-18c).

When glycolysis produces pyruvic acid faster than it can be utilized by the mitochondria, pyruvic acid levels rise in the sarcoplasm. Under these conditions, pyruvic acid is converted to lactic acid, a related three-carbon molecule.

The anaerobic process of glycolysis enables the cell to generate additional ATP when the mitochondria are unable to meet the current energy demands. However, anaerobic energy production has its drawbacks:

• Lactic acid is an organic acid that in body fluids dissociates into a hydrogen ion and a negatively charged lactate ion. The production of lactic acid can therefore lower the intracellular pH. Buffers in the sarcoplasm can resist pH shifts, but these defenses are limited. Eventually, changes in pH will alter the functional characteristics of key enzymes. The muscle fiber then cannot continue to contract.
• Glycolysis is a relatively inefficient way to generate ATP. Under anaerobic conditions, each glucose molecule generates 2 pyruvic acid molecules, which are converted to lactic acid. In return, the cell gains 2 ATP through glycolysis. Had those 2 pyruvic acid molecules been catabolized aerobically in a mitochondrion, the cell would have gained 34 additional ATP.

Muscle Fatigue

A skeletal muscle fiber is said to be fatigued when it can no longer contract despite continued neural stimulation. The cause of muscle fatigue varies with the level of muscle activity. After short peak levels of activity, such as running a 100-meter dash, fatigue may result from the exhaustion of ATP and CP reserves or from the drop in pH that accompanies the buildup of lactic acid. After prolonged exertion, such as running a marathon, fatigue may involve physical damage to the sarcoplasmic reticulum that interferes with the regulation of intracellular Ca²⁺ concentrations. Muscle fatigue is cumulative--the effects become more pronounced as more muscle fibers are affected. The result is a gradual reduction in the capabilities of the entire skeletal muscle.

If the muscle fiber is contracting at moderate levels and ATP demands can be met through aerobic metabolism, fatigue will not occur until glycogen, lipid, and amino acid reserves are depleted. This type of fatigue affects the muscles of long-distance athletes, such as marathon runners, after hours of exertion.

When a muscle produces a sudden, intense burst of activity at peak levels, most of the ATP is provided by glycolysis. After just seconds to minutes, the rising lactic acid levels lower the tissue pH, and the muscle can no longer function normally. Athletes who run sprints, such as the 100-meter dash, get this type of muscle fatigue. We will return to the topics of fatigue, athletic training, and metabolic activity later in the chapter.

Normal muscle function requires (1) substantial intracellular energy reserves, (2) a normal circulatory supply, and (3) a normal blood oxygen concentration. Anything that interferes with one or more of those factors will promote premature muscle fatigue. For example, reduced blood flow from tight clothing, a circulatory disorder, or loss of blood slows the delivery of oxygen and nutrients, accelerates the buildup of lactic acid, and promotes muscle fatigue.

The Recovery Period

When a muscle fiber contracts, the conditions in the sarcoplasm are changed. Energy reserves are consumed, heat is released, and, if the contraction was at peak levels, lactic acid is generated. In the recovery period, the conditions in muscle fibers are returned to normal, preexertion levels. It may take several hours for muscle fibers to recover from a period of moderate activity. After sustained activity at higher levels, complete recovery can take a week.

Lactic Acid Removal and Recycling Glycolysis enables a skeletal muscle to continue contracting even when mitochondrial activity is limited by the availability of oxygen. As we have seen, however, lactic acid production is not an ideal way to generate ATP. It squanders the glucose reserves of the muscle fibers, and it is potentially dangerous because lactic acid can alter the pH of the blood and tissues.

During the recovery period, when oxygen is available in abundance, that lactic acid can be recycled by conversion back to pyruvic acid. The pyruvic acid can then be used either by mitochondria to generate ATP or as a substrate for enzyme pathways that synthesize glucose and rebuild glycogen reserves.

During a period of exertion, lactic acid diffuses out of the muscle fibers and into the bloodstream. This process continues after the exertion has ended, because intracellular lactic acid concentrations are still relatively high. The liver absorbs the lactic acid and converts it to pyruvic acid. Roughly 30 percent of these pyruvic acid molecules are broken down in the TCA cycle, providing the ATP needed to convert the other pyruvic acid molecules to glucose. (We shall cover these processes more fully in Chapter 25.) The glucose molecules are then released into the circulation, where they are absorbed by skeletal muscle fibers and used to rebuild their glycogen reserves. This shuffling of lactic acid to the liver and glucose back to muscle cells is called the Cori cycle.

The Oxygen Debt During the recovery period, oxygen is readily available and the body's oxygen demand remains elevated above normal resting levels. The recovery period is powered by the ATP that aerobic metabolism generates. The more ATP required, the more oxygen will be needed. The oxygen debt, or excess postexercise oxygen consumption (EPOC), created during exercise is the amount of oxygen needed to restore normal, preexertion conditions. Skeletal muscle fibers, which must restore ATP, creatine phosphate, and glycogen concentrations to their former levels, and liver cells, which generate the ATP needed to convert excess lactic acid to glucose, are responsible for most of the additional oxygen consumption. However, several other tissues also increase their rate of oxygen consumption and ATP generation during the recovery period. For example, sweat glands increase their secretory activity until normal body temperature is restored. While the oxygen debt is being repaid, the breathing rate and depth are increased. As a result, you continue to breathe heavily long after you stop exercising.

Heat Loss Muscular activity generates substantial amounts of heat. When a catabolic reaction occurs, such as the breakdown of glycogen or the reactions of glycolysis, the muscle fiber captures only a portion of the released energy. The rest is released as heat. A resting muscle fiber relying on aerobic metabolism captures about 42 percent of the energy released in catabolism. The other 58 percent warms the sarcoplasm, interstitial fluid, and circulating blood. Active skeletal muscles release roughly 85 percent of the heat needed to maintain normal body temperature.

When muscles become active, their consumption of energy skyrockets. As anaerobic energy production becomes the primary method of ATP generation, muscle fibers become less efficient at capturing energy. At peak levels of exertion, only about 30 percent of the released energy is captured as ATP; the remaining 70 percent warms the muscle and surrounding tissues. Body temperature soon climbs, and heat loss at the skin accelerates through mechanisms introduced in Chapters 1 and 5.

Hormones and Muscle Metabolism

Metabolic activities in skeletal muscle fibers are adjusted by hormones of the endocrine system. Growth hormone from the pituitary gland and testosterone (the primary sex hormone in males) stimulate the synthesis of contractile proteins and the enlargement of skeletal muscles. Thyroid hormones elevate the rate of energy consumption by resting and active skeletal muscles. During a sudden crisis, hormones of the adrenal gland, notably epinephrine (adrenaline), stimulate muscle metabolism and increase both the duration of stimulation and the force of contraction. We shall further examine the effects of hormones on muscle and other tissues in Chapter 18.