How McArdle’s Disease Works – A Model

An Illustrated Model of McArdle’s Disease

The image below (credit: this web page) illustrates how McArdle’s disease causes someone to run out of energy during physical exertion.

How Skeletal Muscles Normally Contract A McArdle’s Disease Model
1. Acetylcholine is released from a motor nerve. This causes an entry of calcium into the muscle cell. 1. Acetylcholine is released from a motor nerve. This causes an entry of calcium into the muscle cell.
2. Calcium activates phosphorylase kinase – the first protein kinase discovered by Fischer and Krebs. 2. Calcium activates phosphorylase kinase – the first protein kinase discovered by Fischer and Krebs.
3. Phosphorylase kinase phosphorylates phosphorylase, which is activated 3. Phosphorylase kinase phosphorylates phosphorylase, which is missing or otherwise non-functional
4. Glycogen is broken to glucose. This is used to generate ATP 4. Glycogen is unable to be broken down, creating glucose (and ATP) shortage.
5. The muscle works and requires energy in the form of ATP 5. Motor proteins attach to muscle fibers require ATP for movement.
6. The muscle contains muscle cells 6. Muscles stop responding in absence of ATP .
7. Contractile proteins in the muscle are activated by calcium 7. Because ATP is required to both contract and relax muscles, injury can occur.
The illustration on the left and accompanying explanation are taken from material from the 1992 Physiology or Medicine Nobel Prize Poster displayed on this web page. Credits for that poster are here. The image at right is based on that illustration and represents a theoretical model of how disrupted energy metabolism leads to muscular failure in McArdle’s disease symptom onset.

Contracting muscle cells require large amounts of glucose to create the ATP energy for muscle contraction during strenuous activities. Because glucose cannot be provided quickly enough, muscle cells abruptly run out of energy.

McArdle’s Disease is an “Energy Bottleneck”

In McArdle’s Disease, the metabolism of glycogen to glucose does not take place. Because the concentration of glucose in the cell becomes the limiting factor in the formation of ATP needed for muscular contractions, a bottleneck occurs, called “glycogen debt”. This is similar to what a marathon runner may experience after 20 miles or so, when their leg muscles are completely depleted of glycogen and stop responding. ATP powers the concentric and eccentric movement of muscle fibers (contracting and relaxing movements), which is illustrated in a video here of the sliding filament model.

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