The myoplasm contains most of the creatine phosphokinase, but a small amount can also be found near the M line in the thick filament. This creatine phosphokinase in the thick filament aids in the rapid resynthesis of ATP close to the myosin heads during muscle contraction. However, the amount of phosphate created is only about five times larger than the ATP store, so it cannot sustain prolonged periods of contraction (less than a minute of maximal muscle activity). Skeletal muscle fatigue during intense exercise occurs when the creatine phosphate store is depleted, but this does not necessarily mean that the fatigue is solely caused by this depletion. The muscle cell replenishes the creatine phosphate pool during recovery from fatigue by using ATP produced through oxidative phosphorylation, as the creatine phosphokinase-catalyzed reaction is reversible.

Muscle cells possess glycogen, which can be metabolized during muscle contraction to provide glucose for oxidative phosphorylation and glycolysis. Both of these processes generate ATP to replenish the ATP store. Muscle cells can also take up glucose from the blood, a process that is stimulated by insulin. The cytosolic enzyme phosphorylase releases glucose 1-phosphate residues from glycogen, which are then metabolized through a combination of glycolysis in the cytosol and oxidative phosphorylation in the mitochondria. This yields approximately 37 mol of ATP per mole of glucose 1-phosphate. Blood glucose, on the other hand, yields 36 mol of ATP per mole of glucose due to the usage of 1 ATP to phosphorylate glucose at the beginning of glycolysis. However, these ATP yields depend on a sufficient supply of oxygen. Under anaerobic conditions, the metabolism of glycogen and glucose only yields 3 and 2 mol of ATP per mole of glucose 1-phosphate and glucose, respectively, along with 2 mol of lactate. Depletion of glycogen stores in the muscle is associated with muscle fatigue during prolonged exercise.

During prolonged exercise, fatty acids serve as an important source of energy for muscle cells. Muscle cells contain fatty acids, but they can also take up fatty acids from the blood. Additionally, muscle cells can store triglycerides, which can be hydrolyzed to produce fatty acids when needed. Within the mitochondria, fatty acids undergo β oxidation. To enter the mitochondria, fatty acids are converted to acylcarnitine in the cytosol and then transported into the mitochondria, where they are converted to acyl coenzyme A (CoA). Within the mitochondria, the acyl CoA undergoes β oxidation and produces acetyl CoA, which enters the citric acid cycle and ultimately generates ATP.

If the energy demands of exercise cannot be met through oxidative phosphorylation, an oxygen debt is incurred. After completing exercise, respiration remains above the resting level in order to repay this oxygen debt. The extra oxygen consumption during the recovery phase is utilized to restore metabolite levels (such as creatine phosphate and ATP) and to metabolize the lactate produced by glycolysis. The increased cardiac and respiratory work during recovery also contributes to the higher oxygen consumption observed at this time, which explains why more oxygen needs to be repaid than was borrowed. Even with low levels of exercise, some oxygen debt occurs because slow oxidative motor units consume a significant amount of ATP derived from creatine phosphate or glycolysis before oxidative metabolism can increase ATP production to meet steady-state requirements. The oxygen debt is much greater during strenuous exercise when fast glycolytic motor units are utilized. The oxygen debt is roughly equivalent to the energy consumed during exercise minus that supplied by oxidative metabolism.
Although much of the creatine phosphokinase is present in the myoplasm, a small amount is located in the thick filament (near the M line). The creatine phosphokinase in the thick filament may participate in the rapid resynthesis of ATP near the myosin heads during muscle contraction. The phosphate store created, however, is only about five times the size of the ATP store and thus cannot support prolonged periods of contraction (less than a minute of maximal muscle activity). Skeletal muscle fatigue during intense exercise is associated with depletion of the creatine phosphate store, although as described subsequently, this does not necessarily imply that the fatigue is caused by depletion of the creatine phosphate store. Because the creatine phosphokinase–catalyzed reaction is reversible, the muscle cell replenishes the creatine phosphate pool during recovery from fatigue by using ATP synthesized through oxidative phosphorylation.
Muscle cells contain glycogen, which can be metabolized during muscle contraction to provide glucose for oxidative phosphorylation and glycolysis, both of which generate ATP to replenish the ATP store. Muscle cells can also take up glucose from blood, a process that is stimulated by insulin (see
Chapter 39). The cytosolic enzyme phosphory lase releases glucose 1-phosphate residues from glycogen, which are then metabolized by a combination of glycolysis (in the cytosol) and oxidative phosphorylation (in the mitochondria) to yield the equivalent of 37 mol of ATP per mole of glucose 1-phosphate. Blood glucose yields 36 mol of ATP per mole of glucose because 1 ATP is used to phosphorylate glucose at the start of glycolysis. These ATP yields, however, are dependent on an adequate oxygen supply. Under anaerobic conditions, in contrast, metabolism of glycogen and glucose yields only 3 and 2 mol of ATP per mole of glucose 1-phosphate and glucose, respectively (along with 2 mol of lactate). As discussed later, muscle fatigue during prolonged exercise is associated with depletion of glycogen stores in the muscle.
Fatty acids represent an important source of energy for muscle cells during prolonged exercise. Muscle cells contain fatty acids but can also take up fatty acids from blood. In addition, muscle cells can store triglycerides, which can be hydrolyzed when needed to produce fatty acids. The fatty acids are subjected to β oxidation within the mitochondria. For fatty acids to enter the mitochondria, however, they are converted to acylcarnitine in the cytosol and then transported into the mitochondria, where they are converted to acyl coenzyme A (CoA). Within the mitochondria, the acyl CoA is subjected to β oxidation and yields acetyl CoA, which then enters the citric acid cycle and ultimately produces ATP.
If the energy demands of exercise cannot be met by oxidative phosphorylation, an oxygen debt is incurred. After completion of exercise, respiration remains above the resting level in order to “repay” this oxygen debt. The extra oxygen consumption during this recovery phase is used to restore metabolite levels (such as creatine phosphate and ATP) and to metabolize the lactate generated by glycolysis. The increased cardiac and respiratory work during recovery also contributes to the increased oxygen consumption seen at this time and explains why more oxygen has to be “repaid” than was “borrowed.” Some oxygen debt occurs even with low levels of exercise because slow oxidative motor units consume considerable ATP, derived from creatine phosphate or glycolysis, before oxidative metabolism can increase ATP production to meet steady-state requirements. The oxygen debt is much greater with strenuous exercise, when fast glycolytic motor units are used (Fig. 12.18 ). The oxygen debt is approximately equal to the energy consumed during exercise minus that supplied by oxidative metabolism (i.e., the darkand light-colored areas in