Humans store carbohydrate reserves in the form of glycogen. Glycogen is stored at concentrations up to 12% dry weight in the liver. It is produced when supplies of dietary carbohydrate are adequate and its role is to maintain relatively constant concentrations of glucose in the blood between meals. Glycogen is normally metabolized [local] as follows:
Glycogen Synthesis--excess sugar (energy) is stored
Glc-6-P Glc-1-P (phosphoglucomutase)
Glc-1-P + UTP --> UDP-glucose + PPi (UDP-Glucose pyrophosphorylase)
PPi + H2O --> 2 Pi (pyrophosphorylase)
UDP-Glc + (glycogen)n --> UDP + (Glycogen)n+1 (glycogen synthase)
Glycogenolysis --utilizing the energy or C-skeletons in glycogen when needed
1. (Glycogen)n + Pi --> Glc-1-P + (Glycogen)n-1 (glycogen phosphorylase)
Glycogen debranching enzyme removes glycogen's branches thereby permitting glycogen phosphorlyase reaction to go to completion. it also hydrolyzes alpha(1 - 6)linked glycosyl units to yield glucose.
3. Glc-1-P Glc-6-P (phosphoglucomutase)
4. Glc-6-P + H2O Glc + Pi (glucose-6-Pase)
The glucose is then exported from the liver cells into the blood for circulation to cells requiring glucose.
Muscle cells are different than liver in that they store glucose for their own use, rather than for export to other tissues. When the degree of muscle activity or general exercise exceeds the capacity for oxygen to be transported to skeletal muscle, the muscle is unable to carry out oxidative phosphorylation and the inability to convert NADH to NAD+ could halt all ATP production. Under these conditions, muscle cells contain a reserve of high energy phosphate in the form of creatine phosphate. Because creatine phosphate has a greater standard energy of hydrolysis than ATP, it is able to act as a reserve and phosphorylate ADP to ATP [local] by a substrate-level phosphorylation until the cell's supply of creatine phosphate is exhausted.
However, if the period of exercise exceeds the reserve supply of creatine phosphate, the cell must revert to the ancient pathway used by fermenting bacteria. To produce ATP, large amounts of glucose-6-P are produced from the cellular reserves of glycogen and oxidized to pyruvate by glycolysis. This produces a modest amount of ATP. In order to keep the ATP production active, the NADH produced from pyruvate production must be reoxidized to NAD+. To do this muscle cells produce lactic acid from pyruvate using the enzyme lactate dehydrogenase.
Pyruvate + NADH ---> Lactate + NAD+ + H+
The negative consequence of this anaerobic metabolism is that it rapidly consumes muscle reserves of glycogen and produces toxic amounts of lactate and H+, a combination known as lactic acidosis. This condition can perturb the normal pH of the blood. The muscle cell lactate is exported to the blood and circulates to the liver where it is taken up. In the liver it is oxidized to pyruvate and converted back to glucose by the gluconeogenic pathway. The liver glucose is then free to move into the blood and back to muscle cells. This process of recycling lactate is known as the Cori cycle. The buildup of lactate and the accompanying acidosis are often attributed as the reason for muscle cramping [local], but this is a complex physiological phenomenon and the real cause is likely more complex.
Interestingly, it is possible to suffer from lactic acidosis while oxygen supplies in the blood are abundant. There are quite a few inherited metabolic disorders that affect components of the mitochondrial citric acid cycle or oxidative phosphorylation system. These can limit the ability of the muscle cells to produce ATP and trigger the large scale production of lactate to supplement ATP production under conditions of relatively low scale exercise. Additionally, it is possible that a drug can have the unintended consequence of inhibiting DNA replication in mitochondria. Such an example has been found for drugs designed to inhibit replication of the HIV virus that causes Acquired Immuno Deficiency Syndrome. The drug causes a decrease in the number of mitochondria [local] and produces muscle weakness.
