The amount of ATP in skeletal muscle is only sufficient to provide energy for contraction for a few seconds. Consequently, muscle cells have developed multiple mechanisms to regenerate the ATP needed to sustain the contraction-relaxation cycle: (1) by glycolysis, using blood glucose or muscle glycogen, (2) by oxidative phosphorylation, (3) from creatine phosphate, and (4) from two molecules of ADP in a reaction catalyzed by adenylyl kinase (Figure 1).
Fig1. The multiple sources of ATP in muscle.
Skeletal Muscle Contains Large Quantities of Glycogen
The sarcoplasm of skeletal muscle contains large stores of glycogen, located in granules close to the I bands. The release of glucose from glycogen is dependent on a specific muscle glycogen phosphorylase, which can be activated by Ca2+, epinephrine, and AMP. Ca2+ also activates phosphorylase b kinase, allowing glucose mobilization to begin with the initiation of muscle contraction.
Under Aerobic Conditions, Muscle Generates ATP Mainly by Oxidative Phosphorylation
Glucose, derived from the blood glucose or from endogenous glycogen, along with fatty acids, derived from the triacylglycerols of adipose tissue, are the principal substrates used for aerobic metabolism in muscle. Oxidative phosphorylation is the primary mechanism of ATP production in aerobic respiration. Therefore, contracting muscles have a high demand for oxygen. Some muscles, which can be distinguished by their red color, contain the oxygen storage protein myoglobin to protect against oxygen shortfalls.
Creatine Phosphate Constitutes a Major Energy Reserve in Muscle
Creatine kinase, a muscle-specific enzyme with clinical utility in the detection of acute or chronic diseases of muscle, catalyzes the synthesis of creatine phosphate from creatine and ATP (see Figure 1). The equilibrium constant for this reaction is near 1. Hence, when ATP levels are high, formation of creatine phosphate is favored. However, when ATP levels drop, the equilibrium shifts in favor of ATP synthesis at the expense of stored creatine phosphate. Creatine phosphate thus provides a readily available source for a high-energy phosphate group that can be used to regenerate ATP from ADP.
Adenylyl Kinase Serves as a Reserve of Last Resort
ATP synthase is the primary vehicle for regenerating ATP in living cells. However, it can only synthesize ATP from ADP. In order to regenerate ATP from AMP, the latter must first be phosphorylated to form ADP, a process catalyzed by the enzyme adenylyl kinase using ATP as phosphodonor. This enzyme thus can generate two molecules of ADP from one molecule each of AMP and ATP. When other means for regenerating ATP become exhausted and nucleotide triphosphate level plummet, the equilibrium shifts in favor of synthesizing ATP at the expense of ADP. It is important to note that the by-product of this reaction is AMP. Hence, this is only a temporary expedient as the cell can only cannibalize their total adenine nucleotide pool for so long.
