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Columbia researchers shed light on mechanism of muscle fatigue
First, thanks to many of you who sent us the article by Gina Kolata from the New York Times. It is a hot news week, first with this story breaking on Tuesday and also with Roger Clemens and Brian McNamee testifying before a congressional panel on Wednesday. This kind of story on fatigue is right up our alley here at The Science of Sport, and so let's take a look at this and see what it is all about before we get to the Clemens/McNamee hearings.
Why study fatigue?
Since its inception the profession of Exercise Physiology has focused on "fatigue." This is a broad term, and fatigue has many manifestations. We can fatigue during dynamic maximal exercise such as a peak power output test, and we can fatigue during sub-maximal (endurance) exercise. We can also produce muscle fatigue in the lab while contracting a single limb and muscle group, either repeatedly or continuously. So it has many faces, and exercise scientists have been interested in all of these areas for decades. In fact one of the first exercise labs in North America was the Havard Fatigue Lab, and one of their most famous investigations of fatigue involved two dogs, Joe and Sally, who were fed glucose or nothing while running on a treadmill. The scientists were the first to demonstrate in the lab that carbohydrate ingestion during this type of exercise enhances performance.
Great discoveries occur by accident
While a large number of scientists today are interested in what causes fatigue during endurance exercise, the more mechanistic studies focus on actual muscle fatigue---that is, what is actually happening inside the muscle and how that may or may not cause the muscle to stop working as well.
The clinicians at Columbia University were actually interested in congestive heart failure patients. The problem in these patients is that the heart begins to fail as a pump, and the consequence is that things get a bit backed up. The heart becomes more and more filled with blood, thus losing its ability to actually contract and to pump blood, and it was this weakening of the heart that interested Dr. Andrew Marks at Columbia University.
In their quest to understand their heart failure data, they came to realize that certain events at the molecular level contributed to the cardiac fatigue. The problem is that for muscle, either cardiac or skeletal, to contract, we must produce a successful chain of events. In short, a nerve signal reaches the muscle and stimulates the release of calcium (Ca2+). The calcium is what is actually causing the process of muscle contraction. A special part of the muscle called the sarcoplasmic reticulum, or SR for short, releases calcium, flooding the muscle cells with it. The calcium causes muscle contraction to happen, and when we want to relax the muscle the calcium is then pumped back into the SR, thus causing relaxation of the muscle.
The key to Marks' findings is that his group showed the calcium channels were "leaky," and so the calcium was not reaching its target of the muscle cells. The result was that the muscle could not produce the required amount of force, and in the case of the congestive heart failure patients the consequence of this is that the heart begins to fail in its job as a pump.
Translation - from the lab to the "field"
Calcium blocking drugs were originally developed to lower blood pressure, but Marks' lab altered a calcium-blocking drug so that it was a bit less effective. The result appeared to be a drug that shores up the "leaky" channels. Then they exercised mice for 21 days, with one group receiving the drug and one group a placebo. Both groups showed fatigue over the 21 days, which was measured with a continual treadmill run. However the mice that received the drug ran 13 min longer on the 21st day---77 vs. 64 min for the placebo mice.
To help support this finding, Marks' then collaborated with Dr. David Nieman at Appalachian State University in Boone, NC. The drug cannot be administered to human subjects as it has not yet been approved by the FDA, and so Nieman and Marks instead demonstrated that after cycling three days in row for three hours at 70% VO2max, the cyclists had leaky calcium channels. This suggests that, just like the mice during their 21 day training program, the cyclists were becoming fatigued.
The full pdf file is available to everyone and can be downloaded here. Be warned, however. . .even for scientists it is highly specific, and with all of the special abbreviations and acronyms it might take a while to sift thru!
What on earth does this mean???
So will athletes be taking an "anti-fatigue" drug in the near future? Not likely. . .it will take time before Marks' new drug will become available for use in humans. Clinical trails take years to complete, but more telling is the quote by Dr. W. Robb McClellan from UCLA: "In heart failure, there are three medications that improve mortality, but there have probably been 10 times that many tested." So the odds are against a new drug for this condition, and even if it is approved, WADA and other anti-doping organizations would likely include it on their list of banned substances.
For now what we all must do is follow the development of this drug and see how the clinical trials play out. The problem is that fatigue is such a complex event. . .even if the drug prevents the calcium channels from leaking, that is no guarantee that it will enhance performance during self-paced exercise such as road racing and cycling.
Come back tomorrow for our analysis of Clemens' and McNamee's testimony!
First, thanks to many of you who sent us the article by Gina Kolata from the New York Times. It is a hot news week, first with this story breaking on Tuesday and also with Roger Clemens and Brian McNamee testifying before a congressional panel on Wednesday. This kind of story on fatigue is right up our alley here at The Science of Sport, and so let's take a look at this and see what it is all about before we get to the Clemens/McNamee hearings.
Why study fatigue?
Since its inception the profession of Exercise Physiology has focused on "fatigue." This is a broad term, and fatigue has many manifestations. We can fatigue during dynamic maximal exercise such as a peak power output test, and we can fatigue during sub-maximal (endurance) exercise. We can also produce muscle fatigue in the lab while contracting a single limb and muscle group, either repeatedly or continuously. So it has many faces, and exercise scientists have been interested in all of these areas for decades. In fact one of the first exercise labs in North America was the Havard Fatigue Lab, and one of their most famous investigations of fatigue involved two dogs, Joe and Sally, who were fed glucose or nothing while running on a treadmill. The scientists were the first to demonstrate in the lab that carbohydrate ingestion during this type of exercise enhances performance.
Great discoveries occur by accident
While a large number of scientists today are interested in what causes fatigue during endurance exercise, the more mechanistic studies focus on actual muscle fatigue---that is, what is actually happening inside the muscle and how that may or may not cause the muscle to stop working as well.
The clinicians at Columbia University were actually interested in congestive heart failure patients. The problem in these patients is that the heart begins to fail as a pump, and the consequence is that things get a bit backed up. The heart becomes more and more filled with blood, thus losing its ability to actually contract and to pump blood, and it was this weakening of the heart that interested Dr. Andrew Marks at Columbia University.
In their quest to understand their heart failure data, they came to realize that certain events at the molecular level contributed to the cardiac fatigue. The problem is that for muscle, either cardiac or skeletal, to contract, we must produce a successful chain of events. In short, a nerve signal reaches the muscle and stimulates the release of calcium (Ca2+). The calcium is what is actually causing the process of muscle contraction. A special part of the muscle called the sarcoplasmic reticulum, or SR for short, releases calcium, flooding the muscle cells with it. The calcium causes muscle contraction to happen, and when we want to relax the muscle the calcium is then pumped back into the SR, thus causing relaxation of the muscle.
The key to Marks' findings is that his group showed the calcium channels were "leaky," and so the calcium was not reaching its target of the muscle cells. The result was that the muscle could not produce the required amount of force, and in the case of the congestive heart failure patients the consequence of this is that the heart begins to fail in its job as a pump.
Translation - from the lab to the "field"
Calcium blocking drugs were originally developed to lower blood pressure, but Marks' lab altered a calcium-blocking drug so that it was a bit less effective. The result appeared to be a drug that shores up the "leaky" channels. Then they exercised mice for 21 days, with one group receiving the drug and one group a placebo. Both groups showed fatigue over the 21 days, which was measured with a continual treadmill run. However the mice that received the drug ran 13 min longer on the 21st day---77 vs. 64 min for the placebo mice.
To help support this finding, Marks' then collaborated with Dr. David Nieman at Appalachian State University in Boone, NC. The drug cannot be administered to human subjects as it has not yet been approved by the FDA, and so Nieman and Marks instead demonstrated that after cycling three days in row for three hours at 70% VO2max, the cyclists had leaky calcium channels. This suggests that, just like the mice during their 21 day training program, the cyclists were becoming fatigued.
The full pdf file is available to everyone and can be downloaded here. Be warned, however. . .even for scientists it is highly specific, and with all of the special abbreviations and acronyms it might take a while to sift thru!
What on earth does this mean???
So will athletes be taking an "anti-fatigue" drug in the near future? Not likely. . .it will take time before Marks' new drug will become available for use in humans. Clinical trails take years to complete, but more telling is the quote by Dr. W. Robb McClellan from UCLA: "In heart failure, there are three medications that improve mortality, but there have probably been 10 times that many tested." So the odds are against a new drug for this condition, and even if it is approved, WADA and other anti-doping organizations would likely include it on their list of banned substances.
For now what we all must do is follow the development of this drug and see how the clinical trials play out. The problem is that fatigue is such a complex event. . .even if the drug prevents the calcium channels from leaking, that is no guarantee that it will enhance performance during self-paced exercise such as road racing and cycling.
Come back tomorrow for our analysis of Clemens' and McNamee's testimony!
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