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Thursday, February 14, 2008

Fatigue: A mechanistic breakthrough

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!


Chris said...

you might be interested in this NYT article on cramp too:



Alan said...

If I'm not mistaken, caffeine in large enough doses acts on the Ca2+ transport pathways to delay the onset of fatigue.

Anonymous said...

The article mentioned that muscle fatigue evidently affects all creatures. If it is so easy to circumvent, it must serve some physiological purpose, otherwise animals with leak-proof calcium channels would have taken over earth long ago.

Anonymous said...

Gents, what did you think of the NYT article on cramping?

Ross Tucker and Jonathan Dugas said...

Hi everyone

Thanks for the comments and suggestions and questions. Apologies for the delay in answering. I'll try get them all.

I saw the article on cramping, and while it was good that that knowledge finally made it to the mainstream media, there was nothing in there that we didn't cover in our own series on cramps last year - it was in November, if I'm not mistaken, in a great deal of detail, so that might be worth looking at if you're at all interested. We got a question from someone suggesting that the Ca2+ leaking might also contribute to cramps, rather than K+. I doubt it, neither is the cause, and we explain that in the series we did on the cramps. If calcium or any other electrolyte is involved, there's no evidence for it.

On the note of this particular study, it has been hyped up considerably, and I have to caution against simply believing that calcium is the cause of all the fatigue you experience. That's how it's been portrayed, but it's not entirely true. I'll do a post tomorrow in which I look at the study with a bit more a critical eye, rather than simply summarizing it.

It is a great study, make no mistake, but it's not the answer, 100%. There are things that this does NOT explain, and they need to considered. But unfortunately, what's happened is that the media has presented this finding as the SOLUTION - one solution to everything, which is not true. So I'll do a post tomorrow looking at the missing pieces, and perhaps the most important part of all that this calcium finding can't explain, because I'm not as convinced it's the answer everyone is proclaiming it to be.

Finally, the caffeine point is interesting, because the evidence that caffeine improves performance is very, very weak. In combination with CNS stimulants, like ephedrine, there's an effect, for sure, but by itself, very shaky evidence, especially when the athlete is allowed to pace themselves, which is all important. So again, that is a key point, I'll touch on it in tomorrow's post.

But thanks for everyone for the interest in this study - just to repeat, it's NOT the solution, only part of it, and hopefully we can illustrate that tomorrow.


Ross Tucker and Jonathan Dugas said...

Thanks to those who have chimed in here. All have made valid points.

Just to follow up on what Ross just said. . .it is indeed just a tiny piece of the larger puzzle.

In another comments section I made the point that most often in science we tend to take a reductionist approach to problems, most of the time for necessary reasons. This study is a perfect example of that approach as the leaky calcium channels are being halied as the cause of muscle fatigue, and if only we can prevent those leakages, then "presto," we prevent fatigue.

But as we always try to emphasize here on The Science of Sport, our physiology (and fatigue) is much more complex than just one simple variable. If the leaky channels were the sole cause, then preventing the leaks should prevent fatigue, not just reduce it, as was shown in their mice.

Unfortunately the one result of this approach and the subsequent story that makes it to the lay press is that we get athletes who will now think that taking calcium supplements will help them prevent fatigue. This sounds far fetched, but I have seen this mentioned in discussions.

So again, it is a great study, and deserves its place in PNAS, a prestigious and well know scientific publication. But as Ross said, it is jsut one piece of the puzzle, and many more factors play important roles in fatigue. the authors demonstrated a molecular event, and while it is important data, the bigger picture is a bit more complex.

Kind Regards,

Anonymous said...

Nice article, but please heed other poster's comments and don't buy into a magic bullet theory. There are a number of receptor systems in the body, and in skeletal muscle, that also modulate calcium flux, not just the ryanodine receptor family. Mucking up one system alters cellular balance, which is often compensated for by a parallel or redundant system.

Ross Tucker and Jonathan Dugas said...

Hi Anonymous

Thanks for the comments. In our defence, the "other posters" you are referring to are in fact us!

I (Ross) first posted a comment saying that this study was not by itself the answer, and Jonathan followed by saying it's only a small piece in a much bigger puzzle.

So we're 100% aware of it and we are the last people who will buy into the magic bullet theory. In fact, i'd go so far as to say that this "breakthrough", while exciting, is a long way from actually explaining what happens during exercise.

So not only is it a piece of the puzzle, it's an incomplete piece too. And in my post, I promised an article looking at it, and it will be done in due course.


Anonymous said...

Please do a series on Delayed Onset Muscle stiffness in the same way as you offered the science behind fatigue and cramping.

Is there any evidence that neuromuscular fatigue plays a role in DOMS

Ross Tucker and Jonathan Dugas said...

HI Jenny

Great idea, will do! The plan is to do a post or two more on running shoes (see our posts from about a week ago), then I'm planning a series on pacing strategy and fatigue, and how the brain regulates fatigue. That is a pretty big series, maybe 2 weeks, and then we'll do DOMS.

Thanks for the suggestion.


Chris said...

Pacing strategies : I saw this interesting study and put it on my blog if you are interested:

pacing strategies

Ross Tucker and Jonathan Dugas said...

Hi Chris

Thanks for that - nice one, an interesting study. I had actually read it, I did my PhD on pacing and so I'm in the process of writing a review of all the literature on pacing in different events, what works best and so on?

You might also be interested in sutdies by Carl Foster, and also Jos de Koning. They've done work very similar to this - it's pretty well established now that when you do short duration exercise (less than maybe 4 minutes), the best performance comes from a faster start, even if you slow down at the end. In longer duration exercise, the better strategy is even-paced, possibly even a negative split.

But that'll all come out in the series, when I eventually get around to it!