Glycogen

In the human body, glycogen is a branched polymer of glucose stored mainly in the liver and the skeletal muscle that supplies glucose to the blood stream during fasting periods and to the muscle cells during muscle contraction. Glycogen has been identified in other tissues such as brain, heart, kidney, adipose tissue, and erythrocytes, but glycogen function in these tissues is mostly unknown. Glycogen synthesis requires a series of reactions that include glucose entrance into the cell through transporters, phosphorylation of glucose to glucose 6-phosphate, isomerization to glucose 1-phosphate, and formation of uridine 5ʹ-diphosphate-glucose, which is the direct glucose donor for glycogen synthesis. Glycogenin catalyzes the formation of a short glucose polymer that is extended by the action of glycogen synthase. Glycogen branching enzyme introduces branch points in the glycogen particle at even intervals. Laforin and malin are proteins involved in glycogen assembly but their specific function remains elusive in humans. Glycogen is accumulated in the liver primarily during the postprandial period and in the skeletal muscle predominantly after exercise. In the cytosol, glycogen breakdown or glycogenolysis is carried out by two enzymes, glycogen phosphorylase which releases glucose 1-phosphate from the linear chains of glycogen, and glycogen debranching enzyme which untangles the branch points. In the lysosomes, glycogen degradation is catalyzed by α-glucosidase. The glucose 6-phosphatase system catalyzes the dephosphorylation of glucose 6-phosphate to glucose, a necessary step for free glucose to leave the cell. Mutations in the genes encoding the enzymes involved in glycogen metabolism cause glycogen storage diseases.

Clinical relevance

Disorders of glycogen metabolism

The most common disease in which glycogen metabolism becomes abnormal is diabetes, in which, because of abnormal amounts of insulin, liver glycogen can be abnormally accumulated or depleted. Restoration of normal glucose metabolism usually normalizes glycogen metabolism, as well.

In hypoglycemia caused by excessive insulin, liver glycogen levels are high, but the high insulin levels prevent the glycogenolysis necessary to maintain normal blood sugar levels. Glucagon is a common treatment for this type of hypoglycemia.

Various inborn errors of carbohydrate metabolism are caused by deficiencies of enzymes or transport proteins necessary for glycogen synthesis or breakdown. These are collectively referred to as glycogen storage diseases.

Glycogen depletion and endurance exercise

Long-distance athletes, such as marathon runners, cross-country skiers, and cyclists, often experience glycogen depletion. Almost all of the athlete's glycogen stores are depleted after long periods of exertion without sufficient carbohydrate consumption. This phenomenon is referred to as "hitting the wall" in running and "bonking" in cycling.

Glycogen depletion can be forestalled in three possible ways:

First, during exercise, carbohydrates with the highest possible rate of conversion to blood glucose (high glycemic index) are ingested continuously. The best possible outcome of this strategy replaces about 35% of glucose consumed at heart rates above about 80% of the maximum.

Second, through endurance training adaptations and specialized regimens (e.g. fasting, low-intensity endurance training), the body can condition type I muscle fibers to improve both fuel use efficiency and workload capacity to increase the percentage of fatty acids used as fuel, sparing carbohydrate use from all sources.

Third, by consuming large quantities of carbohydrates after depleting glycogen stores as a result of exercise or diet, the body can increase storage capacity of intramuscular glycogen stores. This process is known as carbohydrate loading. In general, glycemic index of carbohydrate source does not matter since muscular insulin sensitivity is increased as a result of temporary glycogen depletion.

When athletes ingest both carbohydrate and caffeine following exhaustive exercise, their glycogen stores tend to be replenished more rapidly; however, the minimum dose of caffeine at which there is a clinically significant effect on glycogen repletion has not been established.

Glycogen and sport

Muscle glycogen is an important fuel source during exercise. Inadequate glycogen availability results in reduced endurance exercise capacity and an inability to continue exercise.

The body breaks down most carbohydrates (CHO) from the foods we eat and converts them to a type of sugar called glucose. Glucose is the main source of fuel for our cells. Glycogen is the stored form of glucose (made up of many connected glucose molecules).

Glycogen is stored in the muscles and liver When the body needs a quick boost of energy or when the body isn't getting glucose from food, glycogen is broken down to release glucose into the bloodstream to be used as fuel for the cells.

Storage

Glycogen is the molecular form of carbohydrates stored in humans and other mammals. A glycogen particles in skeletal muscles can contain as much as 50,000 glucose units. In humans the majority of glycogen is stored in skeletal muscles (∼500 g) and the liver (∼100 g).

Approximately 80% of the glycogen is stored in skeletal muscles, simply because skeletal muscles account for ∼40–50% of body weight.

The liver has a higher glycogen concentration, but as the liver is much smaller (∼1.5 kg) the total amount of liver glycogen is ∼100 g.

Other tissue, like the heart and brain contains minor glycogen stores with important physiological function.

Image 2: Glucose metabolism and various forms of it in the process. Glucose-containing compounds are digested and taken up by the body in the intestines, including starch, glycogen, disaccharides and as monosaccharide. Glucose is stored in mainly the liver and muscles as glycogen. It is distributed and utilized in tissues as free glucose.

While glycogen provides a ready source of energy, it is quite bulky with heavy water content, so the body cannot store much of it for long. Fats however can serve as a larger and more long-term energy reserve. Fats pack together tightly without water and store far greater amounts of energy in a reduced space.[4]

Sarcolema

Muscle Storage Glycogen: The spherical glycogen molecules are located in three distinct subcellular compartments within skeletal muscle:

intermyofibrillar glycogen, which accounts for approximately three-quarters of total glycogen and is situated near mitochondria between the myofibrils.

subsarcolemmal glycogen, which accounts for ∼5–15% of all glycogen, and

intramyofibrillar glycogen, which also accounts for ∼5–15% of total glycogen. During prolonged exercise, glycogen in all three compartments is used but only intramyofibrillar glycogen becomes depleted.

Function

A main function of glycogen is to maintain a physiological blood glucose concentration, but only liver glycogen directly contributes to release of glucose into the blood. Liver glycogen content decreases rapidly during fasting and the liver glycogen content decreases by ∼65% after 24 h fasting.

Skeletal muscles are unable to release glucose (because muscles lack glucose 6-phosphatase) and muscles glycogen is mainly a local energy substrate for exercise (rather than an energy source to maintain blood glucose concentration during fasting).

In the heart and the brain, glycogen is also an energy substrate that can generate anaerobic energy during short-term oxygen deficiency contributing to survival[3].

Image 4: A diagram of regulation of blood sugar through negative feedback and conversion of glucose to/from glycogen.

1.       Schweitzer GG, Kearney ML, Mittendorfer B. Muscle glycogen: where did you come from, where did you go?. The Journal of physiology. 2017 May 1;595(9):2771.Available:https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP273536 (accessed 20.11.2021)

2.     ↑ Teenshealth Definition Glycogen Available:https://kidshealth.org/en/teens/glycogen.html (accessed 19.11.2021)

3.     ↑ ^{Jump up to:3.0 3.1} Jensen J, Rustad PI, Kolnes AJ, Lai YC. The role of skeletal muscle glycogen breakdown for regulation of insulin sensitivity by exercise. Frontiers in physiology. 2011 Dec 30;2:112.Available:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248697/ Accessed 19.11.2021

4.     ↑ Maricopa Lidids Available:https://open.maricopa.edu/nutritionessentials/chapter/lipids/ (accessed 20.11.2021)

5.     ↑ POGO Nutrition for recovery of endurance activity Available:https://www.pogophysio.com.au/blog/nutrition-for-recovery-of-endurance-activity/ (accessed 20.11.2021)

6.     ↑ Burke LM, Cox GR, Cummings NK, Desbrow B. Guidelines for daily carbohydrate intake. Sports medicine. 2001 Apr;31(4):267-99. Available: https://link.springer.com/article/10.2165/00007256-200131040-00003(accessed 20.11.2021)

7.     ↑ Ivy JL. Regulation of muscle glycogen repletion, muscle protein synthesis and repair following exercise. Journal of sports science & medicine. 2004 Sep;3(3):131.Available:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905295/ (accessed 19.11.2021)

1.      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802397/

a.      Chikwana V.M., Khanna M., Baskaran S. Structural basis for 2ʹ-phosphate incorporation into glycogen by glycogen synthase. Proc. Natl. Acad. Sci. U. S. A. 2013;110(52):20976–20981. [PMC free article] [PubMed] [Google Scholar]

b.      De Giorgis V., Veggiotti P. GLUT1 deficiency syndrome 2013: current state of the art. Seizure. 2013;22(10):803–811. [PubMed] [Google Scholar]

c.       Scholl-Bürgi S., Höller A., Pichler K., Michel M., Haberlandt E., Karall D. Ketogenic diets in patients with inherited metabolic disorders. J. Inherit. Metab. Dis. 2015;38(4):765–773. [PubMed] [Google Scholar]

d.      Gottesman I., Mandarino L., Gerich J. Estimation and kinetic analysis of insulin-independent glucose uptake in human subjects. Am. J. Physiol. 1983;244(6):E632–E635. [PubMed] [Google Scholar]

e.      Lauritzen H.P., Schertzer J.D. Measuring GLUT4 translocation in mature muscle fibers. Am. J. Physiol. Endocrinol. Metab. 2010;299(2):E169–E179. [PubMed] [Google Scholar]