Those of us who suffer the affects of the Post-Polio Syndrome know about fatigue. We often experience overwhelming fatigue, especially in particular muscles affected by polio. When a physician performs manual muscle tests on PPS patients they often seem puzzled because they expect to detect weakness.
But if the patient gives a good effort at contracting muscle against resistance, using all their available muscle fibers, typically the clinician observes good strength in the muscle. For a normal person this effort would use only a fraction of available muscle fibers for this short test. So a physician may be confused because most or all of the available fibers contract completely in PPS as well as in normals. Each viable muscle fiber contracts or doesn't but when it contracts it contracts completely. If there are enough fibers there will be good instant strength against the resistance. But if one continues to contract the same fibers without a reserve of extra fibers to allow for rest, the dearth of fibers will fatigue along with incompletely innervated fibers present in PPS.
"The first thing I thought of was... all of us with PPS. A 10% to 20% improvement in muscle endurance could take us from exhaustion to comfort. And maybe, just maybe, new drugs of a similar type could do even better in the near future."
So fatigue is a proximate cause of PPS symptoms, and whether a person can produce a good instant power against resistance isn't an indicator of this. As a matter of fact polio damaged muscles with too few fibers will not be strong or even able to produce normal instant strength if enough fibers are missing even though the individual does not have symptomatic PPS. But in PPS something happens, probably at the synapses, and fatigue generation in muscle fibers is enhanced because of biochemical changes that occur inside the muscle.
Damaged motor nerves cannot transmit signals back to the brain. They propagate electrochemical signals to the muscles and the signals always move away from the brain. So pain and feelings of fatigue are not the result of neuron damage directly, but of muscle fiber insufficiency to maintain contraction over time. If localized muscle fatigue is a proximate event in symptomatic PPS the problems of PPS patients then are often the secondary symptoms which derive from muscle fatigue. Symptoms such as pain, generalized fatigue, muscle spasms, and exhaustion can result from faulty biochemical signaling of depleted or partially innervated myofibrils in muscle.
PPS fatigue is the result of muscle fibers that are overworked to the point of exhaustion because there aren't enough properly functioning fibers to carry the load. In athletes that overdo training a similar situation arises. They have enough myofibrils but the load is so high in their work during training that their muscle fibers undergo a similar fate to that in PPS muscle fibers. In their case, though, it is the overabundance of work that precipitates the muscle changes in normal numbers of healthy fibers that leads to fatigue. If the athlete really over uses and over trains there will need to be a period of prolonged rest to get the muscle fibers back to their homeostatic condition with all the components, chemical and physical, back in balance. Rest relieves PPS muscle fatigue and general fatigue and also over training fatigue in athletes.
Although in PPS the same biology inside the muscle causes fatigue as in athletes, and the fatigue is relieved in the same way with rest, the load of normal daily tasks would not be excessive if enough undamaged fibers were present. But with PPS there often aren't enough healthy muscle fibers for many to carry out the activities of daily living. Nevertheless, since there are so few fibers to do the job they are working with the same over intensity and invoke the changes that occur in over trained athletes.
A recent paper has both shed light on the biological changes that occur within muscle cells during the process of fatigue and points directly to a drug class that may halt the changes that result in fatigue in muscle cells. Dr. Andrew Marks, a research scientist at the Columbia University College of Physicians and Surgeons in New York, and chair of the Department of Cellular Physiology and Biophysics, published a recent paper in the Proceedings of the National Academy of Sciences which sheds light on what happens inside a muscle fiber during fatigue and how it may be ameliorated and treated. 
Mark's research interests brought him to cardiology early in his career, specifically toward working out the questions involved in how heart muscle fatigues and leads to heart failure. Marks focused on the process of calcium moving inside heart muscle cells and how this calcium transport back and forth within cardiac muscle cells results in fatigue and disease in some patients. When this happens in the heart, smooth muscle builds up inside arteries of the heart, narrowing them and remodeling the heart which causes heart disease. As a result of this work Marks was instrumental in producing the first drug eluting stents that could be inserted into the coronary arteries to widen them and allow for increased blood flow. These stents are used routinely today.
His research interest in heart muscle led Marks to study how muscle contracts at the biochemical level and how continuing contraction (as hearts must do) results in fatigue. Here I will try to simplify the technical concepts that Marks began to understand and which led to his ideas about muscle fatigue, and what followed: ways to improve the process. There is an abundance of calcium inside muscle cells, both cardiac muscle and voluntary skeletal muscle. Before contraction this calcium is released from one part of the muscle fiber and is transported via a channel (a calcium channel) to a receptor which triggers muscle contraction. Marks was able to manufacture, in the laboratory, the receptor that calcium triggered to induce muscle contraction so he could study the process more intensely in the lab. He actually cloned and collected the calcium receptor.
When a muscle contracts a protein called calstabin binds to this calcium receptor. Marks found that a faulty biochemical reaction resulted in poor binding of calstabin to the calcium receptor and worsened heart failure by reducing the capacity of the muscle to resist fatigue. Prior to the year 2000 most muscle researchers felt fatigue was a result of lactic acid accumulating in muscle. However, there were problems with this explanation not the least of which was that lactic acid dissipates very quickly in muscle and the model didn't lead to any understanding of how lactic acid induced fatigue. Since then, because of Marks' and others, attention has turned to the faulty movement of calcium in cells as the genesis of muscle fatigue.
In the failing heart, it has been shown that when calcium doesn't bind to the receptor the way it should this causes some calcium to leak from its channel lessening the supply of calcium to properly contract muscle. The result is fatigue and eventually exhaustion. Marks entertained the idea that skeletal muscle fatigue may be caused by a similar mechanism and he used mice, swimming one group to exhaustion while another control group of mice rested. After muscle biopsies on the overworked mice he found the same leaky calcium channels he found in heart muscle failure. Subsequently Marks showed in human over trained cyclists the same changes, leaky calcium channels, that required days of rest to recover, and it occurred in their muscles exactly as it did in the exercised mice. Marks and his team went on to develop a drug which caused calstabin to bind more tightly to the calcium channels. When the drug was given to mice it was observed that the mice could run 10% to 20% longer on a treadmill than control mice postponing fatigue. The first group to react to this news was athletes and trainers hoping to use the drug to improve athletic performance. They think they've found a new way to use drugging without anabolic steroids to improve athletic performance.
The first thing I thought of was all of us with PPS. A 10% to 20% improvement in muscle endurance could take us from exhaustion to comfort. And maybe, just maybe, new drugs of a similar type could do even better in the near future.
- Wehrens, X. H., Lehnart, S. E., Reiken, S., Vest, J. A., Wronska, A. & Marks, A. R. (2006) Proc. Natl. Acad. Sci. USA 103, 511 518.
- Marks, A. R., Tempst, P., Kwang, H., Taubman,M., Chadwick, C., Inui, M., Fleischer, S. & Nadal-Ginard, B. (1989) Molecular cloning and characterization of the ryanodine receptor/junctional channel complex cDNA from skeletal muscle sarcoplasmic reticulum Proc. Natl. Acad. Sci. USA 86, 86.83-8687
- Youngsteadt, Elsa, The Tiredness of the Long Distance Runner. ScienceNOW Daily News, February, 12, 2008
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